European Journal of Applied Physiology

https://doi.org/10.1007/s00421-020-04360-2

INVITED REVIEW

The impact of statins on physical activity and exercise capacity:

an overview of the evidence, mechanisms, and recommendations
Allyson M. Schweitzer1 · Molly A. Gingrich1 · Thomas J. Hawke1   · Irena A. Rebalka1

Received: 22 December 2019 / Accepted: 24 March 2020

© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract
Purpose  Statins are among the most widely prescribed medications worldwide. Considered the ‘gold-standard’ treatment
for cardiovascular disease (CVD), statins inhibit HMG-CoA reductase to ultimately reduce serum LDL-cholesterol lev-
els. Unfortunately, the main adverse event of statin use is the development of muscle-associated problems, referred to as
SAMS (statin-associated muscle symptoms). While regular moderate physical activity also decreases CVD risk, there is
apprehension that physical activity may induce and/or exacerbate SAMS. While much work has gone into identifying the
epidemiology of SAMS, only recent research has focused on the extent to which these muscle symptoms are accompanied
by functional declines. The purpose of this review is to provide an overview of possible mechanisms underlying SAMS and
summarize current evidence regarding the relationship between statin treatment, physical activity, exercise capacity, and
SAMS development.
Methods  PubMed and Google Scholar databases were used to search the most relevant and up-to-date peer-reviewed research
on the topic.
Results  The mechanism(s) behind SAMS, including altered mitochondrial metabolism, reduced coenzyme Q10 levels,
reduced vitamin D levels, impaired calcium homeostasis, elevated extracellular glutamate, and genetic polymorphisms, still
lack consensus and remain up for debate. Our summation of the evidence leads us to suggest that the etiology of SAMS
development is likely multifactorial. Our review also demonstrates that there is limited evidence for statins impairing exercise
adaptations or reducing exercise capacity for the majority of the investigated populations.
Conclusion  The available evidence indicates that the benefits of engaging in physical activity while on statin medication
largely outweigh the risks.

Keywords  Statins · Exercise · HMG CoA reductase inhibitor · Cardiovascular disease · Myalgia · Myopathy · SAMS ·
Stain-induced muscle symptoms

Abbreviations CVD Cardiovascular disease

ADP Adenosine diphosphate ETC Electron transport chain
ATP Adenosine triphosphate HIV Human immunodeficiency virus
BMI Body mass index HMG-CoA 3-Hydroxy-3-methylglutaryl coenzyme A
CK Creatine kinase LDL-C Low-density lipoprotein cholesterol
CoQ10 Co-enzyme Q10 mPTP Mitochondrial permeability transition pore
CRF Cardiorespiratory fitness O2− Superoxide
CSEP Canadian Society for Exercise Physiology PGC-1α Peroxisome proliferator-activated receptor
gamma coactivator 1-alpha
ROS Reactive oxygen species
Communicated by Michael Lindinger. SAMS Statin-associated muscle symptoms
SERCA​ Sarco-endoplasmic reticulum calcium
* Thomas J. Hawke
hawke@mcmaster.ca ATPase
SNPs Single nucleotide polymorphisms
1
Department of Pathology and Molecular Medicine, 4N65
Health Sciences Centre, McMaster University, 1200 Main
Street West, Hamilton, ON L8N 3Z5, Canada

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Introduction
Cardiovascular disease (CVD) is the number one cause
of death worldwide (Benjamin et al. 2019). As a chronic
illness, CVD develops gradually over the lifespan, and
symptoms often manifest into a diagnosis around mid-
dle age. Given this typically slow progression, risk factor
identification and modification have become a key aspect
of disease prevention. Lifestyle modifications such as con-
suming a healthy diet and participating in regular physi-
cal activity are two well-defined and modifiable factors
that greatly reduce one’s risk of cardiovascular mortality
(Artinian et al. 2010; Kubota et al. 2017). In addition to
these lifestyle modifications, prescription pharmaceuticals
have been demonstrated to reduce cardiovascular-related
mortality. The most commonly prescribed class of phar-
maceuticals for the primary and secondary prevention of
CVD are the 3-hydroxy-3-methylglutaryl coenzyme A
(HMG-CoA) reductase inhibitors, collectively referred to
as statins (Hennessy et al. 2016; Pencina et al. 2014).
The role of statins in CVD prevention centers on their
ability to reduce total systemic cholesterol circulation.
Statins are competitive inhibitors of HMG-CoA reduc-
tase, a key rate-limiting enzyme in the synthesis of the
cholesterol precursor molecule mevalonate (Schachter
2005; Ward et al. 2019). Additionally, statin therapy has
been demonstrated to upregulate low-density lipopro-
tein cholesterol (LDL-C) receptors in peripheral tissues,
further lowering total cholesterol circulation (Istvan and
Deisenhofer 2001). The effects of statin therapy on LDL-C
reduction and subsequent decreases in CVD-associated
mortalities have been widely demonstrated (Downs et al.
1998; Yusuf et al. 2016; Pedersen et al. 2004; Zhou and
Liao 2010). The efficacy of statin therapy noted in these
clinical trials has led to widespread statin prescriptions,
with approximately 1 in 4 North American adults being
recommended statin therapy (Gu et al. 2014; Hennessy
et al. 2016; Pencina et al. 2014).
Though generally well tolerated, up to 29% of statin
users develop statin-associated muscle symptoms (SAMS)
(Fernandez et  al. 2011; Sathasivam and Lecky 2008),
including muscle pain (myalgia), inflammation (myositis),
damage (myopathy), and in extreme cases, rhabdomyolysis
(Bruckert et al. 2005; El-Salem et al. 2011; Pasternak et al.
2002; Thompson et al. 2016). Despite reports implicating
the ‘nocebo effect’ in many SAMS cases (Finegold et al.
2014; Gupta et al. 2017), the cessation of these symp-
toms is often only achieved through statin discontinuation
(Cohen et al. 2012; Colivicchi et al. 2007). Of the SAMS,
myalgia is by far the most common complaint (Ramkumar,
Raghunath and Raghunath 2016), presenting as muscle
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European Journal of Applied Physiology
soreness, weakness, cramps, and aches in the upper and/
or lower extremities. Given that regular physical activ-
ity significantly reduces the risk of CVD development,
progression, and mortality (Artinian et al 2010; Oja et al.
2017; Paffenbarger, Blair and Lee 2001; Sharman, La
Gerche and Coombes 2015; Thompson et al. 2003), it is
also a concern to note that exercise may induce and/or
exacerbate SAMS (Bruckert et al. 2005; Thompson et al.
1997). In fact, statin prescription is widely associated with
a reduction in physical activity levels, with similar con-
clusions drawn by 3 large observational studies (Lee et al.
2014; Loenneke and Loprinzi 2018; Scott et al. 2009).
Whether this reduction in physical activity is directly or
indirectly associated with statin use, however, is unclear.
Overall, statin users were found to perform less moder-
ate and vigorous physical activity compared to non-users,
had increased sedentary behaviour, averaged significantly
fewer steps per day than non-users, and had reduced odds
of engaging in muscle-strengthening activities. Overall,
the aforementioned muscle-associated complications are
the predominant reason for whole-class statin non-compli-
ance (Cohen et al. 2012; Colivicchi et al. 2007; McGinnis
et al. 2007; Zhang, Plutzky and Turchin 2013), highlight-
ing a major clinical obstacle in the reduction of CVD risk.
Despite its clinical relevance, the underlying
mechanism(s) of SAMS are inconclusive, and there is a
lack of consensus on the combined benefits of statins and
physical activity; both individually highlighted to profoundly
reduce CVD risk. This review aims to summarize the most
prominent hypothesized mechanisms of statin-induced alter-
ations to skeletal muscle metabolism and their subsequent
implications on SAMS. The effect of statins on aerobic and
anaerobic training capacity will also be examined. Lastly,
the safety of physical activity and statin co-prescription
in both the general population of statin users and those at
higher risk of SAMS will be evaluated.
Proposed mechanisms for SAMS
While a number of statin-induced alterations to skeletal
muscle metabolism have been proposed, a collective, con-
clusive, mechanistic origin for all SAMS remains elusive.
Below are several of the most prominent proposed mecha-
nisms explaining the etiology of SAMS: altered mitochon-
drial metabolism, reduced coenzyme Q10 levels, reduced
vitamin D levels, disrupted calcium homeostasis, disrupted
glutamate homeostasis, and genetic single nucleotide poly-
morphisms (SNPs) (Fig. 1).
European Journal of Applied Physiology
Fig. 1  Schematic of the proposed statin-induced alterations to skel-
etal muscle and vasculature in relation to SAMS, as discussed in this
review. Statins enter the circulation and reduce serum coenzyme Q10
and vitamin D concentrations. It is unclear whether these reductions
in serum levels result in reduced intramuscular levels. Statins have
been demonstrated to increase ROS production as well as decrease
mitochondrial respiration and ATP production within the myofiber.
An increased antioxidant demand as a result of statin treatment has
been demonstrated to increase xCT transporter content/activity as
well as increase concentrations of extracellular glutamate. SERCA
activity has been demonstrated to increase in asymptomatic but not
symptomatic statin users compared to non-users and may contribute
to the impaired calcium homeostasis demonstrated in statin users.
CLC-1 chloride channel content has been demonstrated to be reduced
in statin users and has been implicated to reduce the membrane sta-
Mitochondrial metabolism
The mitochondria are the primary source of energy in ani-
mal cells that undergo aerobic metabolism (Dykens and Will
2008). This energy, in the form of adenosine triphosphate
(ATP), is integral for numerous cell processes including
membrane transport, cell signaling, and, specific to mus-
cle, contraction. As they are extremely metabolically active,
mature skeletal muscle cells (myofibers) require large, con-
tinuous supplies of ATP to survive and are host to an abun-
dance of mitochondria. Mitochondria create ATP through
oxidative phosphorylation via the electron transport chain
(ETC), a series of electron-transferring complexes located
on the inner mitochondrial membrane. This transfer of
electrons creates an electrical gradient whose energy is har-
nessed to combine adenosine diphosphate (ADP) with an
inorganic phosphate to create ATP.
One consequence of ETC activity is the production of
free radicals, referred to as reactive oxygen species (ROS).
In modest amounts, ROS play an important role in many
cellular processes including myofiber repair (Branch 1998;
Hamanaka and Chandel 2010; Nunes-Silva et al. 2014; Rhee
bility of statin users’ myofibers. References supporting each mecha-
nism correspond to the superscript numbers within the figure and are
detailed below. 1, Banach et al. (2015), Berthold et al. (2006), Mar-
coff and Thompson (2007), McMurray et al. (2010), Morrison et al.
(2016), Taylor et  al. 2015); Qu et  al. (2018). 2, Eisen et  al. (2014),
Khayznikov et  al. (2015), Kurnik et  al. (2012), Michalska-Kasiczak
et  al. (2015), Parker et  al. (2013), Riphagen et  al. (2012), Wu et  al.
(2018). 3, Camerino et  al. (2017). 4, Busanello et  al. (2018), du
Souich et  al. 2017). 5, Allard et  al. (2018), Bouitbir et  al. (2016),
Busanello et  al. (2017), Davies et  al. (1982), Pryor (1982), Rebalka
et  al. (2019). 6, Allard et  al. (2018), Bouitbir et  al. 2016, Busanello
et  al. (2017), Davies et  al. (1982), Dohlmann et  al. (2019), Pryor
(1982), Rebalka et  al. (2019). 7, Allard et  al. (2018). 8, Camerino
et al. (2017). 9, Rebalka et al. (2019)
et al. 2000; Sena and Chandel 2012); however, when there is
imbalance, excess ROS generates oxidative stress and dam-
age within the cell. The most common free radical produced
by the ETC is superoxide (­ O2−) (Brand 2010). The unpaired
electron present on each ­O2− moiety is able to readily accept
electrons from surrounding proteins, subsequently oxidizing
and altering their function and activity.
Endogenous and exogenous antioxidants act to will-
ingly donate their electrons to ROS to reduce the poten-
tial for oxidative cellular damage. Antioxidant homeosta-
sis can become disrupted, however, during exceptional
circumstances such as physical activity or in response to
xenobiotics; synthetic chemicals that are not produced
by the body including statins and zidovudine (Dykens
and Will 2008; Kline et al. 2009). Statins in particular
have been demonstrated to reduce mitochondrial respi-
ration and increase ROS production (Allard et al. 2018;
Bouitbir et al. 2016; Busanello et al. 2017; Davies et al.
1982; Pryor 1982; Rebalka et  al. 2019). Allard et  al.
(2018) demonstrated that muscle from symptomatic sta-
tin users had reductions in complex II and IV activity and
an approximate 28% decrease in ATP production capacity
13

compared to muscle from non-statin users. Additionally,
Dohlmann et al. (2019) demonstrated reduced complex II
respiration in both symptomatic and asymptomatic statin
users. When ETC respiration capacity was normalized
to mitochondrial content, respiratory capacity was also
reduced in both symptomatic and asymptomatic statin
users (Busanello et al. 2017). Reduced mitochondrial res-
piration rates can cause electrons to leak from the ETC
(Hamanaka and Chandel 2010; Panajatovic et al. 2019),
thereby reducing the electrical gradient and subsequent
ATP production. If the myofiber is consistently unable to
meet its energy requirements, apoptotic pathways may be
initiated. This concept is a proposed mechanism of statin-
induced myofiber death. Additionally, electrons that leak
from the ETC promptly react in the oxygen-rich surround-
ings to form ­O2− and increase ROS production. Given that
exercise increases mitochondrial ROS production, if ROS
is a contributor to SAMS, it is of concern that exercise
may exacerbate or induce these symptoms. This concern
is addressed in further detail below.
Contrasting the increased ROS production, exercise also
evokes a number of mitochondrial adaptions that posi-
tively affect the muscle’s response to statins. One of these
adaptations is the upregulation of peroxisome proliferator-
activated receptor gamma coactivator 1-alpha (PGC-1α)
activity, the primary regulator of mitochondrial biogenesis
that has recently been implicated to mitigate the effects of
statin myotoxicity on mitochondrial health. In a murine
model, Panajatovic et al. (2019) demonstrate that skeletal
muscle overexpression of PGC-1α protects against statin-
induced mitochondrial alterations and rescues functional
measures such as reduced distance run to exhaustion.
PGC-1α has been shown to regulate the expression of
several endogenous antioxidant proteins and reduce ROS
production, lending cause to its positive effects on mito-
chondrial health when overexpressed (Baar et al. 2002;
St-Pierre et al. 2003). Additionally, Zoladz et al. (2016)
assessed mitochondrial bioenergetics in rats following 8
weeks of endurance training. Interestingly, the authors
present that ROS production is reduced in active muscle
and increased in resting muscle following endurance train-
ing. The authors suggest that these changes may contribute
to increased mitochondria efficiency in active muscle, as
well as signal for muscle remodeling and enhance mito-
chondrial function in resting muscle. While this preclinical
evidence demonstrates a therapeutic role of exercise on
SAMS, more research is required before definitive conclu-
sions can be drawn in humans.
In addition to skeletal muscle mitochondria, statins
have also been demonstrated to alter the metabolism of
mitochondria in the vascular endothelium (Broniarek and
Jarmuszkiewicz 2018). Atorvastatin treatment in  vitro
was demonstrated to decrease endothelial mitochondrial
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European Journal of Applied Physiology
oxidation rates and increase ROS production. The authors
also suggest that these alterations are highly calcium
dependent, may indirectly affect the skeletal muscle, and
may contribute to the toxicity demonstrated with statin
treatment.
Evidence within the literature supports that statin use
increases mitochondrial-mediated oxidative stress through
reduced mitochondrial respiration. Whether these alterations
affect functional measures is discussed below. Given that not
all statin-users suffer from SAMS, there are likely additional
contributing factors in excess of alterations to mitochondrial
capacity that predispose one to their development. Some of
these additional factors are proposed below.
Coenzyme Q10
Co-enzyme Q10 (CoQ10) is a fat-soluble, vitamin-like sub-
stance that is ubiquitously expressed throughout the human
body (James et al. 2004). When reduced to ubiquinol, it pro-
tects cells against free radical-facilitated oxidative stress and
is a cofactor for ETC electron transfer (James et al. 2004).
It has been widely reported that statin users have reduced
plasma CoQ10 levels (Banach et al. 2015; Berthold et al.
2006; Marcoff and Thompson 2007; McMurray et al. 2010;
Morrison et al. 2016; Taylor et al. 2015; Qu et al. 2018).
This can be attributed to the attenuation of mevalonate pro-
duction via statin use, subsequently attenuating farnesyl
pyrophosphate and CoQ10 production (James et al. 2004).
Additionally, as CoQ10 is systemically transported in con-
junction with LDL, statin-induced reductions in total LDL
content may also reduce systemic CoQ10 transport (James
et al. 2004). Due to its roles within the mitochondria, it was
hypothesized that this lack of CoQ10 may be contributing
to the reduced respiration and increased ROS production
demonstrated in the mitochondria of statin users.
Unsurprisingly, CoQ10 supplementation has been pro-
posed as a treatment for SAMS. Recent literature, however,
demonstrated that while CoQ10 supplementation effectively
increased serum CoQ10 levels, SAMS developed at the same
rate with and without supplementation (Banach et al. 2015;
Bogsrud et al. 2013; Bookstaver et al. 2012; Rott et al. 2016;
Taylor et al. 2015; Young et al. 2007). This lack of symptom
relief may be explained by the absence of change in intra-
muscular CoQ10 levels. Though serum CoQ10 levels are
reduced in statin users, evidence does not support its reduced
presence in the muscle (Busanello et al. 2017; Camerino
et al. 2017), making its contribution to SAMS questionable.
As previously mentioned, SAMS manifestation may be mul-
tifactorial and thus it is unlikely that CoQ10 disruption alone
is the underlying cause of SAMS development.
European Journal of Applied Physiology
Vitamin D
Vitamin D is a fat-soluble vitamin that is well known for
facilitating calcium uptake into bones. In addition to its
role in maintaining bone health, vitamin D has been dem-
onstrated to have an important role in muscle health. Vita-
min D deficiency has been associated with proximal muscle
weakness and myopathy and has been demonstrated to play
a role in intracellular myofiber calcium homeostasis (Caruso
and Fuzaylov 2013; Girgis et al. 2013; Glerup et al. 2000;
Rasheed et al. 2013). Furthermore, vitamin D has been dem-
onstrated to enhance the hepatic and intestinal production
of cytochrome P450 3A4, a key enzyme in statin metabo-
lism (Lynch and Price 2007; Wang et al. 2013). Accord-
ingly, reduced vitamin D levels can reduce statin metabolism
and clearance, resulting in a greater chance for myotoxicity
(Ahmed et al. 2009; Glueck et al. 2011a, b; Glueck et al.
2011a, b; Pérez-Castrillón et al. 2010).
A meta-analysis investigating the association between
vitamin D and SAMS found that statin users with SAMS
had significantly lower plasma vitamin D levels than asymp-
tomatic statin users (Michalska-Kasiczak et al. 2015). In
contrast, however, several studies report no significant
differences in vitamin D levels between symptomatic and
asymptomatic statin users or no increases in SAMS with
vitamin D deficiency (Eisen et al. 2014; Kurnik et al. 2012;
Parker et al. 2013; Riphagen et al. 2012). Wu et al. (2018)
tested the effects of vitamin D supplementation on statin
adherence and found no effect over a 24-month period, while
Khayznikov et al. (2015) found previously statin-intolerant
patients to be free of SAMS after 24 months of vitamin
D supplementation. Overall, while statins seem to reduce
serum vitamin D levels, the muscle-specific role of vitamin
D in SAMS is largely unknown.
Calcium homeostasis
Calcium, through its reversible binding with thin-filament
troponin, plays an essential role in both skeletal muscle con-
traction and relaxation. Due to these roles, calcium is also
a viable factor involved in producing SAMS, which include
muscle spasms and cramping.
Calcium’s re-uptake into the sarcoplasmic reticulum
offers a mechanism for spasm and cramping. If calcium
remains in high concentrations within the sarcoplasm, cross-
bridge cycling and muscle contraction will persist (Berchtold
et al. 2000; Ebashi and Endo 1968; Gollnick et al. 1991).
The primary pump responsible for calcium reuptake into the
sarcoplasmic reticulum is sarco-endoplasmic reticulum cal-
cium ATPase (SERCA) (MacLennan et al. 1985). Camerino
et al. (2017) found no difference in SERCA gene expres-
sion between statin users and non-statin users; however,
the activity of SERCA in this study was not investigated.
Interestingly, when SERCA activity was assessed in statin
users, activity was 30% higher in asymptomatic users com-
pared to non-users, but no difference was observed between
symptomatic statin users and non-users (Allard et al. 2018).
Past research has demonstrated that simvastatin increases
release of calcium from the mitochondrial permeability
transition pore (mPTP) (du Souich et al. 2017), thus, the
increase in SERCA activity demonstrated in asymptomatic
users may be the compensatory result of this increased sar-
coplasm concentration and, in line with this hypothesis,
statin users who are not able to compensate may develop
SAMS. Alternatively, increased SERCA activity may impair
calcium homeostasis rather than be a compensatory mecha-
nism. SERCA content has been demonstrated to decrease
in human skeletal muscle following 5 weeks of endurance
training; an adaptation that is largely responsible for improv-
ing muscular mechanical efficiency (Majerczak et al. 2008).
If increased SERCA activity does contribute to the impaired
calcium handling demonstrated in statin users, the findings
of Majerczak et al. (2008) suggest that physical activity may
benefit these individuals.
In addition, statin users with SAMS demonstrate a
40% reduction in CLC-1 chloride channel proteins when
compared to non-statin users (Camerino et al. 2017). This
channel is responsible for resting sarcolemma membrane
stability, and thus reductions may lead to membrane hyper-
excitability, and a decreased threshold for subsequent mus-
cle cramping, spasm, and weakness (Camerino et al. 2017;
Jurkat-Rott and Lehmann-Horn 2005). This theory also sug-
gests that since membranes are hyperexcitable, the rate of
force production in statin users may also be greater. Allard
et al. (2018) recently demonstrated that the median current
needed for statin users to produce 30% of their maximal
voluntary contraction was 16% lower than non-statin users;
however, the maximal rate of force development did not dif-
fer between groups. Morville et al. (2019) similarly demon-
strated no differences in rate of force development between
statin users (asymptomatic or symptomatic) and non-users.
Furthermore, Mallinson et  al. (2015) demonstrated that
though maximal force did not differ between statin users and
non-users, statin users took longer to reach this maximum.
Taken together, these results suggest that if a difference in
membrane excitability does exist between statin users and
non-users, other mechanisms might impair contractility
resulting in no functional differences.
When assessed from a functional level, Allard et  al.
(2018) demonstrated that time to relaxation following a
single muscle contraction was lower in asymptomatic and
symptomatic statin users than non-users, counterintuitive
to what the aforementioned SERCA activity data would
suggest. Following continuous contraction, however, statin
users’ muscles took longer to relax and the rate of force
development deceased more rapidly with each consecutive
13

contraction (Allard et al. 2018). This largely suggests that
calcium homeostatic mechanisms may be altered in statin
users as a whole, but that elevated SERCA activity in asymp-
tomatic statin users is insufficient to alter muscle kinetics.
Though the specifics of this mechanism require further
investigation, evidence supports that statins alter calcium
homeostasis, which likely has an effect on the myofiber.
These effects could be direct (alterations to calcium release/
reuptake) or indirect (downstream effects on the mitochon-
dria and ATP production). It has been suggested that statins
alter mPTP permeability and increase mitochondrial calcium
uptake (Busanello et al. 2018). If enough calcium is taken up
by the mitochondria, respiration is impeded, swelling may
occur, and apoptotic/necrotic pathways may be initiated
(Busanello et al. 2018; Marchi et al. 2018; Orrenius et al.
2003; Pinton et al. 2008). This could explain the deficits
in mitochondrial respiration demonstrated in statin users as
well as the reduction in ATP production capacity. In sup-
port of this concept, Busanello et al. (2018) showed that
blocking the mPTP in statin-treated mice restored normal
mitochondrial respiration.
In conclusion, while there appears to be a role for cal-
cium homeostasis in SAMS, identification of the direct and/
or indirect mechanism requires further elucidation. As not
all statin users develop SAMS, a predisposing factor likely
needs to be present for SAMS to arise. This could be a previ-
ously manifested reduced calcium handling capacity, or any
other factor exacerbated by reduced calcium homeostasis
including poor mitochondrial function or impaired antioxi-
dant capacity.
Glutamate
Glutamate is the most abundant excitatory neurotransmit-
ter in the central nervous system and acts as an activator of
both central and peripheral nociceptors. It is also a metaboli-
cally active amino acid in skeletal muscle that is involved
in antioxidant creation and energy metabolism. The distinct
compartmental functions of glutamate make it a very tightly
regulated metabolite. To avoid nociceptor overexcitation,
glutamate has a low interstitial concentration relative to
inside the cell, including muscle cells specifically (Essen-
Gustavsson and Blomstrand 2002; Gerdle et al. 2016; Gra-
ham et al. 2000; Hu et al. 1994; Newsholme et al. 2003;
Pinky et al. 2018). In fact, glutamate has the greatest skeletal
muscle intracellular-to-plasma gradient in the human body
(Bergstrom et al. 1974).
Two distinct transporters have been identified on skeletal
muscle for glutamate transport. System ­X−ag is responsible
for glutamate uptake and system X ­ −c, a cystine-glutamate
antiporter, is responsible for glutamate extrusion (Rutten
et al. 2005). Increases in extracellular glutamate through
upregulation of system X ­ −c activity have been demonstrated
13
European Journal of Applied Physiology
to play a role in cancer-induced bone pain (Ungard, Seidlitz
and Singh 2014). Reinforcing the role of glutamate in noci-
ception, intramuscular injections of glutamate elicit experi-
mental induction of muscle pain (Cairns et al. 2001, 2003;
Svensson et al. 2005), and elevations in the presence of
extracellular glutamate have been found in individuals with
chronic myalgia and pain conditions (Rosendal et al. 2004;
Sarchielli et al. 2007). Furthermore, chronic high levels of
extracellular glutamate can sensitize nociceptors, lowering
their threshold for activation, a process termed long-term
potentiation. Glutamate is implicated to cause long-term
potentiation in pathologies such as fibromyalgia and chronic
pain (Sarchielli et al. 2007).
Rebalka et al. (2019) demonstrated an increase in system
­X−c transporter content and extracellular glutamate follow-
ing statin treatment in vitro. The release of glutamate from
skeletal muscle cells was independent of muscle cell damage
and positively correlated to the concentration and duration of
statin administration. This observation was specific to skel-
etal muscle cells, and similar observations were not observed
in dermal fibroblasts, consistent with the clinical observa-
tion that statin users do not report dermal pain as a side
effect of statin prescription. Furthermore, when system ­X−c
activity was blocked, statin treatment did not cause increases
in extracellular glutamate content. It was hypothesized that
increased system X ­ −c activity was necessary to compensate
for the statin-induced increases in ROS production. Given
that cysteine is required for glutathione synthesis and can-
not be synthesized within the myofiber, it must be imported
from extracellular sources. As such, system ­X−c is upregu-
lated to increase cystine influx, conversion to cysteine, and
subsequent glutathione synthesis. A consequence of the
increased intracellular cysteine is an increase in extracel-
lular glutamate, demonstrated to cause pain perception and/
or long-term potentiation (Rosendal et al. 2004; Sarchielli
et al. 2007). Importantly, the aforementioned pathway offers
a mechanism for pain in the absence of damage, which is
often the case with statin-induced muscle pain. While clini-
cal evidence supports glutamate as a general instigator of
pain, follow-up studies are needed to elucidate whether this
mechanism translates in vivo for SAMS.
SLCO1B1 single nucleotide polymorphism
Properties of xenobiotics including their lipophilicity, half-
life, and clearance/metabolism play a role in their toxic-
ity. SAMS are more likely to occur when taking lipophilic
statins, which do not require active transport to cross cell
membranes (Bruckert et al. 2005; Dale et al. 2007). This
allows lipophilic statins to freely increase both their concen-
tration within the myofiber and their potential for myotoxic-
ity (du Souich et al. 2017; Ward et al. 2019). Furthermore,
lipophilic statins are less readily excreted through the renal
European Journal of Applied Physiology
system which increases their time in circulation (Ward et al.
2019). This is troublesome, as the longer a statin is in circu-
lation, the more likely it is to have toxic effects on peripheral
tissues (Mancini et al. 2011).
All statins go through first-pass clearance in the gut and
are metabolized in the liver. The OATP1B1 transporter
exists on hepatic cells and is responsible for the influx of
xenobiotics (MoBhammer et al. 2014; Romaine et al. 2010).
Importantly, a SNP on the SLCO1B1 gene that encodes this
transporter has been positively correlated with SAMS preva-
lence (Brunham et al. 2012; Carr et al. 2019; DeGorter et al.
2013; Donnelly et al. 2011; Niemi et al. 2004; Niemi 2010;
Santos et al. 2012). This SNP has been indicated to create a
less functional OATP1B1 transporter and thus reduces the
hepatic influx of xenobiotics, including statins (Meyer du
Schwabedissen et al. 2015). This transporter exists on the
liver but not the muscle, and thus muscle influx of xeno-
biotics is unaffected by this SNP (du Souich et al. 2017).
While Hubáček et al. (2015) found no association between
myalgia and the SLCO1B1 variant in a Czech population,
these participants were on low-dose simvastatin or atorvas-
tatin, indicating that dose and statin type may play a role in
this association. These results follow the trends of the previ-
ous sections, suggesting that this SNP may contribute to the
development of SAMS, but in isolation is likely insufficient.
Concluding remarks on the proposed mechanisms
of SAMS
Overall, the literature implicates numerous mechanisms to
be involved in SAMS, the list of which was not exhausted
in this review (see the following reviews for further read-
ing: Bouitbir et al. 2019; Gluba-Brzozka et al. 2016). SAMS
likely present due to a concurrent combination of multiple
mechanisms. This would explain why altering a single vari-
able, as conducted by many of the studies detailed above, is
inadequate to significantly and reproducibly treat SAMS.
Future comprehensive studies are needed to identify which
of the aforementioned variables play a greater contributing
role in the etiology of SAMS.
Effects of statins on muscle regeneration
Statins have been demonstrated to alter the ultrastructure
of skeletal muscle as well as its metabolism (Allard et al.
2018; Busanello et al. 2018; Camerino et al. 2017; Rebalka
et al. 2019). As such, concern arises surrounding muscle
regeneration in statin users; most notably exercise-induced
myofiber injury.
Following eccentrically induced muscle damage, Urso
et al. (2005) found significant alterations to gene expression
in statin users. Many of these altered genes were involved in
the ubiquitin proteasome pathway, protein folding, catabo-
lism, and apoptosis, suggesting that statins may disrupt the
balance between degradation and repair following myofiber
injury (Urso et al. 2005). While no clinical studies directly
assess muscle repair in statin users following exercise, stud-
ies have assessed their serum creatine kinase (CK) levels
(Allard et al. 2018; Bouitbir et al. 2016; Morville et al. 2019;
Parker et al. 2013). Upon sarcolemma damage/disruption,
CK is released from the myofiber, and is, therefore, often
used as a clinical marker to indicate skeletal muscle damage
(Ganga, Slim and Thompson 2014). Intuitively, it is common
for CK to be elevated following strenuous exercise (Parker
et al. 2012). Compared to non-users, Parker et al. (2013) and
Bouitbir et al. (2016) found statin users to have elevated CK
levels at rest, indicating a greater baseline level of muscle
damage. A recent case study also describes the development
of acute rhabdomyolysis in a marathon runner treated with
rosuvastatin, characterized by severe pain and elevated CK
levels (Toussirot et al. 2015). It is important to note, how-
ever, that isolated case studies are ineffective in implicat-
ing statins, as an entire class of pharmaceuticals, in causing
rhabdomyolysis. Similarly, a group of statin-treated amateur
runners had greater increases to serum CK than their statin-
naïve peers after completing the Boston Marathon (Parker
et al. 2012). In this case, increasing age was associated with
higher serum CK levels.
As these aforementioned studies do not directly assess the
impact of statins on tissue repair, preclinical models must be
assessed to draw preliminary conclusions. Two recent stud-
ies found statin-treated animals to have impaired myofiber
regeneration (Otrocka-Domagala and Paździor-Czapula
2018; Rebalka et al. 2017). Rebalka et al. (2017) found that,
following cardiotoxin injection and myofiber lysis, myofiber
area was significantly reduced in mice treated with statins
when compared to their statin-naïve counterparts ten days
post-injury. As a time-course experiment was not completed,
it is not clear if statin-treated muscle regenerated completely.
Complementing this work, Otrocka-Domagala and Paździor-
Czapula (2018) saw similar findings in a statin-treated por-
cine model. After causing muscle necrosis, the inflammatory
response (particularly M1 macrophage activation), demon-
strated by a prolonged presence and degree of inflammation,
was delayed in statin-treated animals. Similar to Rebalka
et al. (2017), this study did not demonstrate whether repair
was delayed or completely impeded. A study by Trapani
et al. (2012) looked later in the time course of muscle repair
in the presence of statin treatment. 21 days following muscle
injury, histology revealed completely restored tibialis ante-
rior muscle architecture in the absence of statin treatment.
Simvastatin treated mice, however, still displayed central
nucleation. Importantly, mevalonate co-therapy negated the
effect of statin treatment, abrogating the presence of central
nuclei and supporting that the observed regenerative delay
13

was a result of reduced cholesterol biosynthesis pathway
entities (Trapani et al. 2012).
Another indication of the effect of statins on muscle repair
can be drawn from in vitro work. Satellite cells, activated
in response to myofiber injury, proliferate and differentiate
into myoblasts to facilitate tissue repair (Hawke and Garry
2001). Geranylgeraniol, downstream of mevalonate in the
cholesterol biosynthesis pathway, has been shown to induce
myogenic differentiation of murine myoblasts derived from
muscle satellite cells and reduce statin-induced muscle cell
damage (Cao et al. 2009; Matsubara et al. 2018). Similarly,
statin treatment has been shown to affect satellite cell dif-
ferentiation and reduce myoblast fusion, attenuating the pro-
duction of multinucleated entities (Baba et al. 2008; Martini
et al. 2009; Trapani et al. 2012). These impairments were
rescued with mevalonate co-treatment, validating the impor-
tance of downstream products of the cholesterol biosynthe-
sis pathway in muscle maturation (Trapani et al. 2012). As
satellite cells are primary mediators of muscle regeneration,
these results are indeed concerning for muscle repair and
regeneration in the presence of statin therapy.
Exercise has many positive effects on both cardiovascu-
lar health and the muscle, and thus may be therapeutic in
itself to many individuals prescribed statins. With aberrant
skeletal muscle regeneration reported as a result of statins,
however, the necessity for repeated skeletal muscle repair
following regular exercise may pose a problem. Taken
together, the above preclinical studies suggest that statins
delay muscle regeneration and impede satellite cell function.
It is recognized that the aforementioned studies use extreme
models of damage that do not represent exercise-induced
damage in humans and the observed delays in repair may
not affect functional measures. Clearly, more research that
evaluates the effects of statins on muscle repair, particularly
exercise-induced damage in humans, must be conducted to
elucidate these effects in humans.
Statins, aerobic metabolism and aerobic
exercise capacity: general population
Poor cardiorespiratory fitness (CRF) has repeatedly been dem-
onstrated as a risk factor for CVD and mortality (Kubota et al.
2017; Myers et al. 2015; O’Donnell and Elosua 2008). Regu-
lar participation in aerobic physical activity is the best way
to improve and maintain strong CRF. As such, an increase in
aerobic physical activity often accompanies a reduction in
CVD risk. The mechanisms behind this phenomenon are not
limited to improved CRF, however. Reduced systolic/diastolic
blood pressure, blood lipids, blood cholesterol, arterial stiff-
ness, resting heart rate, and an increase in stroke volume and
angiogenesis are additional cardiovascular benefits of regular
physical activity (Kubota et al. 2017; Myers et al. 2015). As
13
European Journal of Applied Physiology
an alternative to regular physical activity, statins are extremely
effective in both primary and secondary CVD prevention. As
both statins and aerobic physical activity have compelling evi-
dence in support of their benefits for cardiovascular health, it
has been suggested that combination therapy of the two may
provide additive effects. Concerns arise, however, given that
the predominant negative side effects of statin use are skel-
etal muscle related. As physical activity stresses the muscu-
loskeletal system, there is apprehension that the double-hit of
statins plus exercise may increase the risk of adverse events.
The following information aims to consolidate the current
evidence for an effect of statins on aerobic fitness capacity and
metabolism and to determine whether aerobic physical activ-
ity should be prescribed in combination with statin therapy.
See Table 1 for a summary of this evidence.
To begin, evidence supporting the danger of combina-
tion physical activity and statin treatment must be exam-
ined. A 2005 study by Bruckert et al. is commonly cited as
evidence that SAMS are aggravated by physical activity. In
this study, 40% of the population reporting myalgia indicated
that certain factors triggered their symptoms. Of this 40%,
over half indicated ‘unusual physical exertion’ as a trigger.
Bruckert et al. (2005) also report the prevalence of myalgia
to be greater in physically active individuals. Though com-
pelling, it is important to consider that all participants were
statin users on high-dose statin therapy; the prevalence of
myalgia reported here is likely an overrepresentation of the
prevalence in the general public. Additionally, this study
does not discriminate between aerobic and resistance activ-
ity and only unusual (not regular) physical activity is defined
as a trigger. Thompson et al. (1997) demonstrated serum CK
levels to be elevated in statin users compared to non-users
following treadmill exercise, indicating a greater presence of
muscle damage. These serum CK levels returned to baseline
within 3 days.
Reports that demonstrate myopathy and rhabdomyolysis
following exercise are large contributors to the apprehension
around physical activity and statin use (Parker et al. 2012;
Semple 2012; Toussirot et al. 2015). This type of exercise
is not representative of physical activity that would be pre-
scribed to improve statin users’ cardiovascular health. Thus,
using it as evidence that physical activity is dangerous in
statin users is likely inappropriate. Additionally, rhabdomy-
olysis with statin use occurs in approximately 0.00003% of
the population (Davidson et al. 2006) and presents more
commonly as a result of comorbidities or combined therapy
with other pharmaceuticals (Marot et al. 2000; Ozdemir
et al. 2000; Wu et al. 2009; Yeter et al. 2007).
Multiple studies completed within the past 4 years have
demonstrated that statin treatment does not negatively affect
aerobic capacity (determined by differences in VO2max) or
alter aerobic metabolism (Allard et al. 2018; Matuszek and
Grant 2018; Morville et al. 2019). Morville et al. (2019)
 Table 1  Summary of recent findings from studies investigating exercise interventions in statin users
Study Study design Sample size Participant demograph- Statin type, dose, treat- Aerobic exercise per- Anaerobic exercise SAMS?
ics ment length formance performance

Morville et al. (2019) Cross-sectional 84 Males/females Simvastatin No difference between No difference between N/A
Age: 40–70 years 40 mg/day statin users/non-users statin users/non-users
Average BMI: 28.3 kg/ Statin use for minimum No difference between No difference between
m2 3 months symptomatic/asymp- symptomatic/asymp-
Statin users with/ tomatic statin users tomatic statin users
without SAMS and
non-users
Allard et al. (2018) Cross-sectional 30 Males/females Atorvastatin, fluvas- No difference between No difference between N/A
European Journal of Applied Physiology

Age: 54–68 years tatin, pravastatin, statin-treated/ placebo groups

Average BMI: 26.4 kg/ simvastatin groups
m2 10, 20, or 40 mg/day
Statin users and non- Statin use for minimum
users 3 months
Matuszek and Grant Within-patient control 16 Males/females Atorvastatin, rosuvasta- No difference when on/ N/A N/A
(2018) Age: 39–82 years tin, simvastatin off statin
Average BMI: 28.0 kg/ 10, 20, 40, or 80 mg/
m2 day
Statin users; treatment Statin use average
ceased and reintro- 3.6 years
duced
Baptista, Veríssimo, Randomized control 827 Males/females Atorvastatin, pitavasta- Improved CRF in exer- Improved in exercise No difference between
and Martins (2018) Age: > 60 years tin, pravastatin, rosu- cise group (independ- group (independent groups
Average BMI: 28.8 kg/ vastatin, simvastatin ent of statin use) of statin use)
m2 2, 10, or 20 mg/day
Statin users Statin use for minimum
1 year
Bahls et al. (2017) Cross-sectional 3500 Males/females Not reported Statin use inversely N/A N/A
Age: 20–79 years related to V
­ O2max in
Average BMI: 28.0 kg/ males but not females
m2
Statin users and non-
users
Mallinson et al. (2015) Cross-sectional 18 Males Atorvastatin, simvas- N/A No difference between Myalgia exacerbated in
Age: 69–72 years tatin groups 6/9 participants
Average BMI: N/A 20, 40, or 80 mg/day
Statin users with myal- Statin treatment for
gia and non-users minimum 1 year
Molina-Sotomayoret al. Randomized control 57 Females Lovastatin Improved CRF with N/A N/A
(2018) Age: > 60 years 20 mg/day exercise
Average BMI: N/A Treatment length not
Statin users reported

13


Table 1  (continued)
Study Study design Sample size Participant demograph- Statin type, dose, treat- Aerobic exercise per- Anaerobic exercise SAMS?
ics ment length formance performance

13
Zanetti et al. (2019) Randomised placebo 83 Males/females Rosuvastatin Improved CRF with Improved muscle N/A
control Age: 18–60 years 10 mg/day exercise (independent strength with exercise
Average BMI: 24.5 kg/ 12 weeks of treatment of statin use) (independent of statin
m2 use)
Statin-naïve, hyper-lipi-
demic and cholester-
olemic participants
with HIV diagnosis
for minimum 1 year
Kelly et al. (2016) Randomised control 2331 Males/females Atorvastatin, pravas- Improved CRF with N/A N/A
Age: 45–70 years tatin, simvastatin, exercise (independent
Average BMI: 30.0 kg/ ‘Other lipid lowering’ of statin use)
m2 Statin dose/treatment
Statin users and non- length not reported
users, ejection frac-
tion ≤ 35%
Toyama et al. (2017) Uncontrolled interven- 43 Males/females Not reported Trending towards N/A N/A
tion Age: 63–79 years increased CRF
Average BMI: 24.3 kg/
m2
Statin users with coro-
nary artery disease
Schwellnus et al. Cross-sectional 15,778 Males/females Not reported N/A N/A Statin use and running
(2018) Age: 18 + years experience posi-
Average BMI: N/A tively correlated with
Marathon race entrants exercise-associated
muscle cramping
Loenneke and Loprinzi Cross-sectional 2775 Males/females Atorvastatin, ceriv- N/A No difference between N/A
(2018) Age: 50–85 years astatin, fluvastatin, statin users/non-users
Average BMI: 28.0 kg/ lovastatin, pravasta-
m2 tin, simvastatin
Statin users and non- Treatment dose not
users reported
Statin use average
3 years
European Journal of Applied Physiology
 European Journal of Applied Physiology

and Allard et al. (2018) recruited symptomatic and asymp-

tomatic statin users as well as untreated participants. These
researchers both demonstrated no differences in aerobic
capacity or metabolism between groups. It is unclear if
symptomatic statin user symptoms were exacerbated dur-
ing exercise, though the lack of an aerobic capacity differ-
SAMS?

ence demonstrates that subjects with SAMS did not prema-

No difference between N/A

turely stop activity. Allard et al. (2018) did demonstrate a

statin users/non-users

decrease in ventilatory threshold as well as increased lactate

concentration post-exercise with statin use. This indicates
Anaerobic exercise

that statin users, in particular symptomatic users, may rely

performance

more heavily on anaerobic metabolism during exercise. It is

important to note that the statin-naïve subjects evaluated in
both of these studies were dyslipidemic and, therefore, may
represent a less healthy portion of the population. In compli-
ance with ethical standards, used a within-subjects design,
Aerobic exercise per-

and participants were instructed to cease statin medication

for at least 3 weeks prior to performing submaximal tread-
mill exercise. After recommencing their statins for at least
formance

3 weeks, the same participants repeated the submaximal

Atorvastatin, lovastatin, N/A

exercise test. The investigators demonstrated no differences

in physiological characteristics between visits, including fat
Statin use 0.3–10 years
Sample size Participant demograph- Statin type, dose, treat-

oxidation, carbohydrate oxidation, and lactate concentra-

pravastatin, simvas-

tion. Interestingly, Bahls et al. (2017) demonstrated a nega-

Statin users: 29.9 kg/m2 10, 20, 40 mg/day

tive effect of statins on aerobic capacity in males, but not

ment length

females, indicating that statins may have sex-specific effects.

Given that, for the majority, statin treatment does not
tatin

negatively affect aerobic capacity or metabolism, the abil-

ity of statins to improve aerobic capacity with physical
significantly different

activity was investigated. Baptista et al. (2018) recruited

Statin users and non-
25.4 kg/m2 (*BMI

and assigned participants to 1 of 3 groups: statin interven-

between groups)
Age: 68–72 years

Statin non-users:

tion, statin plus exercise intervention, or exercise interven-

Males/females

Average BMI:

tion alone. The exercise intervention consisted of combined

aerobic (progressive upper and lower extremity movements),
users

anaerobic, and balance training. Participants in both the

ics

exercise and statin plus exercise intervention groups had

improved CRF and functional status, whereas statin treat-
ment alone caused a moderate reduction in these measures.
Importantly, participants did not note any abnormal symp-
24

toms of muscle pain. While these findings demonstrate that

physical activity is safe for statin users and that statins do
not reduce the positive effects of aerobic physical activity,
Cross-sectional

these interventions were conducted in a healthy population

Study design

that would not otherwise be prescribed statins. High choles-

terol levels and/or an elevated risk of metabolic disease may
predispose for greater statin-induced impairments to aerobic
fitness, and these populations should also be investigated.
Though aerobic physical activity has been demonstrated
Table 1  (continued)

Rengo et al. (2016)

as safe for the majority of statin users, many of the afore-

mentioned studies excluded statin users with multiple
comorbidities, and thus the effect of physical activity in
these populations cannot be discussed. In combination, how-
Study

ever, these studies provide evidence that statins do not alter

13

aerobic capacity or mitigate the positive effects of physical
activity. In this light, healthcare professionals should rec-
ommend regular moderate aerobic physical activity, as it is
more likely to have positive, rather than negative, effects.
Similarly, statin users should not avoid aerobic physical
activity in fear of inducing or exacerbating their symptoms
as current evidence demonstrates that regular, moderate
physical activity is unlikely to cause these issues (Allard
et al. 2018; Baptista et al. 2018; Molina-sotomayor et al.
2018; Matuszek and Grant 2018; Morville et al. 2019). If a
patient does withhold from participating in aerobic physical
activity in fear of exacerbating SAMS, or if SAMS present
or become aggravated with aerobic physical activity, it may
be worth considering replacing statin pharmacotherapy with
prescribed aerobic physical activity, which reduces blood
lipids and cholesterol as well (Mann et al. 2014). Addition-
ally, physical activity provides many systemic health ben-
efits that statins cannot, including improved muscle health,
cognitive function, functional capacity, and quality of life
(Baptista et al. 2018; Kubota et al. 2017; McPhee et al. 2016;
Molina-sotomayor et al. 2018; Myers et al. 2015). Overall,
aerobic physical activity should not be avoided until SAMS
are induced or exacerbated, as the benefits of combination
physical activity and statin treatment outweigh the risks of
being an inactive statin user.
Statins and anaerobic exercise function
and capacity: general population
Regular participation in anaerobic or resistance exercise has
been demonstrated to reduce functional declines in muscle
strength associated with aging, improve insulin resistance
and glucose metabolism, reduce body fat, and improve mark-
ers of cardiovascular health (American College of Sports
Medicine Position Stand 1998; Fagard 2006; Hurley and
Hagberg 1998; Kraschnewski et  al. 2016; Mavros et  al.
2017; Patel et al. 2017; Roth et al. 1999; Westcott 2012;
Winett and Carpinelli 2001). The CSEP Canadian Physical
Activity Guidelines recommend 2 days of muscle strength-
ening exercise per week regardless of age (Canadian Society
for Exercise Physiology 2017). Given that statins have been
demonstrated to alter muscle metabolism at the ultrastruc-
tural level, below we discuss the evidence of whether these
changes translate clinically in terms of muscle strength and
function, and whether resistance exercise is effective and
safe for statin users.
Evidence for a reduction in muscle strength with statin
prescription was first noted in a series of case reports from
4 patients in which symptomatic statin users experienced
weakness upon strength testing that reversed when statin
treatment was discontinued (Phillips et al. 2002). Muscle
biopsies from this population indicated abnormal lipid
13
European Journal of Applied Physiology
accumulation and cytochrome-oxidase negative fibers, sug-
gesting an intrinsic muscle deficit rather than weakness due
to neuropathy or decreased physical activity. Interestingly,
both muscle strength and biopsy abnormalities resolved
within 3 to 5 months of cessation of statin therapy. An intrin-
sic muscle defect was also identified in a small study of both
asymptomatic and symptomatic statin users during electri-
cal quadriceps stimulation, further suggesting a deficiency
independent of a neural impairment or of the participant’s
effort or motivation (Allard et al. 2018).
Larger scale studies, however, have not provided evidence
to support an intrinsic loss of muscle strength with statin
prescription (Loenneke and Loprinzi 2018; Scott et al. 2009;
Parker et al. 2013). In particular, there are limited data to
suggest that statins directly impair resistance exercise capac-
ity independent of changes to physical activity levels. Even
when no change to physical activity levels occurred, as in the
interventional STOMP study, statin treatment did not induce
a decrease in either upper or lower limb muscle strength
(Parker et al. 2013). Notably, limited studies have specifi-
cally considered muscle strength differences between symp-
tomatic and asymptomatic statin users. Initial case reports
identifying muscle strength deficits with statin use found that
only symptomatic statin users had losses to muscle strength
independent to changes in physical activity levels (Phillips
et al. 2002). However, a small study by Panza et al. (2016)
failed to confirm these original findings. A more thorough
analysis of muscle strength in combination with simultane-
ous muscle biopsies would clarify to what extent sympto-
matic statin users experience intrinsic muscle defects and
the impact on muscle strength.
In a state-of-the-art placebo-controlled study, Parker et al.
(2013) introduced statin-naïve participants to atorvastatin or
placebo treatment and assessed muscle symptom presenta-
tion and strength. The same proportion of statin and placebo-
treated participants developed myalgia; however, symptom
presentation differed between treatment groups. Symptom
onset was earlier in statin-users and was more localized to
the extremities, whereas symptom presentation was general
whole-body or localized to an area of previous injury in
placebo-treated participants. Statin users with SAMS also
had lower muscle strength in 4 of 15 strength tests. While
muscle ultrastructure was not assessed in this study, it pro-
vides strong evidence for the nocebo effect and suggests that
statins alter muscle physiology enough to affect strength.
Of note, statin treatment did not reduce volitional physical
activity more than placebo treatment; however, differences
between symptomatic and asymptomatic statin users were
not reported.
In compliance with ethical standards, found no differ-
ences in lean body mass, knee extensor or handgrip strength
between statin users and non-users independent of symptom
presentation. Muscle biopsy analysis, however, demonstrated
European Journal of Applied Physiology
that non-users had significantly more type IIX fibers than
statin users. This difference supports previous reports that
statins differentially affect muscle fiber type, however, in the
absence of impeding functional measures. Additional studies
support the findings of no differences in maximal isometric
knee extensor strength between statin users and statin-naïve
subjects (Allard et al. 2018; Mallinson et al. 2015). As the
aforementioned studies demonstrate minimal differences in
strength between subjects, it is inferred that muscle pain,
if present, did not affect muscle strength or exercise capa-
bilities. In combination, these studies suggest that statins’
alterations to skeletal muscle metabolism are insufficient to
cause strength impairments.
Next, it is valuable to determine whether strength gains
and positive adaptations to resistance training are affected
by statin treatment. Notably, two studies have found that
resistance training in combination with statin treatment had
positive effects (Baptista et al. 2018; Zanetti et al. 2019).
Baptista et al. (2018) demonstrate that statin users assigned
to an exercise intervention group improved upper and lower
body limb strength to the same degree as exercising partici-
pants not taking statins. In contrast, statin users that were
not part of the exercise intervention saw declines in func-
tional measures supporting the premise that statin users are
at greater health risk when inactive.
Though well established that statins alter muscle metabo-
lism, the findings from the current analysis do not support
that these alterations translate to systemically impair muscle
strength. Additionally, there is little evidence that resistance
exercise seriously exacerbates SAMS. These findings should
encourage statin users to engage in resistance activity to
improve and/or avoid reductions in functional health. If sta-
tin users are nervous to commence resistance training due to
the possibility of inducing or exacerbating symptoms, they
should be encouraged to avoid unusual exertion and work at
low intensities, as even small increases in activity can have
large positive effects on muscle strength (Deplanque et al.
2012; Heesch et al. 2012; Hupin et al. 2015; Warburton et al.
2006).
Statins, aerobic exercise, and anaerobic
exercise: high‑risk populations
As previously established, current evidence supports that
statins alter skeletal muscle metabolism, but that for the
majority of the population, these alterations are insufficient
to cause clinical changes in aerobic or anaerobic function
and performance. The populations analyzed in this review
thus far have represented the general population of statin
users. This section aims to more closely examine the impact
of statins on physical activity and exercise capacity in higher
risk SAMS populations. Common SAMS risk factors include
comorbid cardiovascular disease and advanced age > 65
(Nguyen et al. 2018).
CVD comorbidity is a risk factor for both myopathy and
rhabdomyolysis (Nguyen et al. 2018) and has been an exclu-
sion criterion in many of the previously examined studies.
Given that this population is one who are largely prescribed
statins, special attention should be given to their exercise
health. In compliance with ethical standards, investigated the
effects of combination statin and aerobic exercise (station-
ary cycling or treadmill running) training in patients with
chronic heart failure and found exercise training to increase
peak oxygen capacity and 6-min walking distance. Impor-
tantly, statin users and non-users saw similar gains with
exercise. Similarly, König et al. (2005) recruited patients
with diagnosed stable coronary heart disease that partici-
pated in regular outpatient exercise groups. These research-
ers demonstrated that in combination, lipid-lowering drugs
and physical activity were more effective at reducing inflam-
matory parameters related to morbidity and mortality than
pharmaceuticals alone. Furthermore, Toyama et al. (2017)
demonstrated that combination statin therapy and aerobic
exercise training in patients with coronary artery disease
did not cause any adverse events, indicating that aerobic
exercise is safe for statin users with coronary artery disease.
Particularly interesting is a recent study which demonstrated
that exercise promotes cardiomyogenesis and extends the
regenerative capacity of the mouse heart following myocar-
dial infarction (Vujic et al. 2018). As cardiomyocyte death
contributes largely to heart failure, this increase in myogen-
esis seen with exercise may have positive implications for
this population of human subjects.
Physical activity is integral for delaying age-related func-
tional declines (McPhee et al. 2016), and statins have been
demonstrated to increase older adults’ risk for sarcopenia
(Herghelegiu et al. 2018). While a potential exacerbation
of the adverse effects of statins has been shown to occur in
the elderly (Golomb 2005; Herghelegiu et al. 2018), this
does not appear to be the case for resistance exercise capac-
ity (Agostini et al. 2007; Mallinson et al. 2015; Panayiotou
et al. 2013; Rengo et al. 2016). While Mallinson et al. (2015)
found that symptomatic statin users did take longer to reach
peak power, resulting in less work output; this was concluded
to be due to joint- and muscle-related discomfort and not
an intrinsic muscle deficit. It is important to highlight that
studying statin-induced muscle deterioration in the elderly is
confounded by the high incidence of muscle dysfunction and
sarcopenia in this population. Pre-existing losses to muscle
mass, quality, and strength may be too pronounced for addi-
tional statin-induced deficits to be identified. Therefore, it
is possible that statins do have a detrimental effect on this
population but those changes may be masked by variability
amongst subjects in their age-induced deficits.
13

To determine whether statin treatment and concomitant
physical activity are safe in the elderly population, Hender-
son et al. (2016) recruited men and women aged 70 to 89 and
at high-risk of mobility disability. Of those recruited, statin
users and non-users were randomly assigned to exercise
intervention (aerobic, resistance, and balance exercises) or
control groups. Aerobic physical activity consisted of 30 min
of walking at a moderate intensity. Following intervention,
it was demonstrated that the exercise group had significantly
reduced onset of mobility disability. Reduced systolic blood
pressure and reduced risk of diabetes, heart attack, stroke,
and peripheral artery disease were also demonstrated with
exercise. Importantly, statin use did not attenuate the posi-
tive impact of exercise and no adverse events were docu-
mented. Similarly, in compliance with ethical standards,
Molina-Sotomayor et  al. demonstrated that progressive
walking training is safe and effective in older women on
statin therapy. Moreover, combination of statin and exercise
therapy proved effective in improving functional status, cho-
lesterol management, and overall cardiovascular health in a
cohort of dyslipidemic older adults whereas statin prescrip-
tion alone negatively affected cardiorespiratory health (Bap-
tista et al. 2018). In conjunction, these studies demonstrate
that physical activity is not only safe but also beneficial for
the elderly population taking statins.
The current evidence does seem to support that extreme
high-intensity exercise may increase the risk of SAMS
(Parker et  al. 2012; Schwellnus et  al. 2018; Toussirot
et al.2015). Importantly, this type of exercise is not repre-
sentative of the type and intensity of physical activity that
would be prescribed for cardiovascular health benefits in
elderly or cardiovascular subjects; those both at greater risk
of SAMS and necessitating statin prescription.
Discussion and conclusion
This review aimed to identify and summarize the current
mechanistic evidence for SAMS and determine if these
mechanisms may lead to alterations in exercise capacity
and performance. Finally, we aimed to elucidate, based on
current evidence, the efficacy and safety of combination sta-
tin and physical activity prescription. Established literature
has demonstrated that statins reduce muscle strength during
strength testing, as well as elevate serum CK both at rest
and after exercise (Bouitbir et al. 2016; Parker et al. 2013;
Parker et al. 2012; Toussirot et al.2015), raising the concern
that physical exertion may exacerbate muscle damage. The
fear surrounding SAMS and physical activity may actually
play a role in nocebo effect that has been demonstrated in
placebo-control studies (Parker et al. 2013), thus we aimed
to determine if this fear was evidence based and should limit
13
European Journal of Applied Physiology
health care professionals from prescribing physical activity
to their statin-prescribed patients.
The current review demonstrates that statins do alter
skeletal muscle metabolism, in particular, mitochondrial
metabolism. The mechanism(s) behind SAMS, however, still
lack consensus. Our summation of the evidence leads us to
suggest that the etiology of SAMS development is likely
multifactorial. Placebo-control trials that manipulate and
control for these multiple variables are, therefore, needed
to further elucidate the mechanism(s) behind SAMS. The
demonstrated alterations to the skeletal muscle at the cellular
level do not, however, appear to cause functional deficits for
the majority of the population; demonstrated by the lack of
differences between statin users and non-users in both anaer-
obic and aerobic physical activity test parameters (Agostini
et al. 2007; Allard et al. 2018; Bahls et al. 2017; Baptista
et al.2018; El-Salem et al. 2011; Henderson et al. 2016; Hen-
nessy et al. 2016; Loenneke and Loprinzi 2018; Mallinson
et al. 2015; Matuszek and Grant 2018; Molina-sotomayor
et al. 2018; Morville et al. 2019; Parker et al. 2013; Rengo
et al. 2016; Scott et al. 2009; Zanetti et al. 2019). Given the
cardiovascular, cognitive, and overall benefits of a physically
active lifestyle, statin users should be encouraged to engage
in regular, moderate level anaerobic and aerobic physical
activity. Physical activity does indeed provide very similar
cardiovascular benefits to statins in terms of blood lipid and
vascular resistance in the absence of negative muscle side
effects (Fig. 2); therefore, it should be prescribed to hyper-
cholesterolemic and dyslipidemic individuals as a first line
of treatment (Fulcher et al. 2018; Kubota et al. 2017; Lefferts
et al. 2018; McPhee et al. 2016; Myers et al. 2015). Alternate
to statin medication, moderate physical activity improves
muscle health at both a structural and functional level. If
statin medication does need to be prescribed, patients should
be encouraged to also engage in regular physical activity.
Health care professionals should aim to reduce fear sur-
rounding physical activity in statin users to encourage a
healthy lifestyle and reduce nocebo effects.
A limitation of many studies included in this review is
that the sample population of statin users recruited had
been receiving statin therapy for extended periods of time.
This may have led to an underrepresentation of SAMS
given that SAMS typically present 4 to 6 weeks after the
initiation of statin treatment (Parker et al. 2013). Addi-
tionally, statin users with more severe SAMS may have
already stopped medication and/or are less prone to par-
ticipate in a study that has the potential to worsen their
symptoms. This would also reduce the treatment effects
demonstrated in these studies. Importantly, however, the
findings of this review indicate that long-term statin users
should not avoid physical activity in fear of inducing or
exacerbating symptoms.
European Journal of Applied Physiology
Fig. 2  Schematic of the benefits (green) and disadvantages (red)
of statin treatment and regular physical activity, as discussed in this
review. References supporting each mechanism correspond to the
superscript numbers within the figure and are detailed below. 1,
Banach et  al. (2015), Berthold et  al. (2006), Bogsrud et  al. (2013),
Bookstaver et  al. (2012), Marcoff and Thompson (2007), Mor-
rison et  al. (2016), Qu et  al. (2018), Rott et  al. (2016), Taylor et  al.
(2015), Young et al. (2007). 2, Bruckert et al. (2005), El-Salem et al.
(2011), Fernandez et al. (2011), Gupta et al. (2017), Pasternak et al.
(2002), Sathasivam and Lecky (2008), Thompson et  al. (2016). 3,
Allard et  al. (2018), Bouitbir et  al. (2016), Busanello et  al. (2017),
Dohlmann et  al. (2019), Mallinson et  al. (2015), Panajatovic et  al.
In conclusion, our review demonstrates that statins do
not impair exercise adaptations or reduce exercise capacity
for the majority of the population. Engaging in anaerobic
and aerobic physical activity is safe and effective for statin
users and should be prescribed as a first line of treatment for
hypercholesterolemic and dyslipidemic individuals as well
as those who are unable to tolerate statin therapy. The evi-
dence that is currently available indicates that the benefits
of engaging in physical activity while on statin medication
largely outweigh the risks.
Funding  This study was funded by the Natural Sciences and Engi-
neering Research Council of Canada (Grant nos. 2018-06324 and
2018-522456).
(2019), Rebalka et  al. (2019). 4, Allard et  al. (2018), Bouitbir et  al.
(2016), Morville et al. (2019), Parker et al. (2013). 5, Artinian et al.
(2010), Hupin et  al. (2015), Kubota et  al. (2017), Oja et  al. (2017),
Paffenbarger et  al. (2001), Sharman et  al. (2015), Thompson et  al.
(2003). 6, Istvan and Deisenhofer (2010), Law et  al. (2003), Zhou
and Liao (2010). 7, Fagard (2006). 8, Lefferts et al. (2018), Zhou and
Liao 2010. 9, Deplanque et  al. (2012), Heesch et  al. (2012), Hupin
et  al. (2015), Mavros et  al. (2017), Warburton et  al. (2006), Winett
and Carpinelli (2001). 10, Myers et  al. (2015), O’Donnell and Elo-
sua (2008), Patel et al. (2017). 11, Oja et al. (2017). 12, Mavros et al.
(2017), Molina-sotomayor et al. (2018), Toyama et al. (2017)
Compliance with ethical standards 
Conflict of interest  The authors declare that they have no conflict of
interest.
Ethical approval  Approval from the institutional review board was not
required for completion of this manuscript.
Informed consent  For this retrospective review, formal consent is not
required.
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