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Received: 21 November 2020    Revised: 1 March 2021    Accepted: 2 March 2021

DOI: 10.1111/1756-185X.14104

REVIEW ARTICLE

The pathophysiological effects of exercise in the management

of idiopathic inflammatory myopathies: A scoping review

Ilke Coskun Benlidayi1  | Latika Gupta2

1
Department of Physical Medicine and
Rehabilitation, Cukurova University Faculty
of Medicine, Adana, Turkey
2
Department of Clinical Immunology and
Rheumatology, Sanjay Gandhi Postgraduate
Institute of Medical Sciences, Lucknow, India
Correspondence
Ilke Coskun Benlidayi, Department of
Physical Medicine and Rehabilitation,
Faculty of Medicine, Cukurova University,
Adana, Turkey.
Email: icbenlidayi@hotmail.com
Abstract
Idiopathic inflammatory myopathy (IIM) is a term used for a heterogeneous group of
diseases characterized by severe muscle weakness. In addition to pharmacological
treatment options, non-­pharmacological methods such as exercising are essential for
proper management of myositis. The present article aimed to provide an insight into
the potential pathophysiological mechanisms underlying exercise-­related benefits in
myositis. A systematic search was performed on PubMed/MEDLINE, Scopus, Web
of Science, and Google Scholar using the following keywords and their combinations:
“idiopathic inflammatory myopathy”, “inflammatory myopathy”, “myositis”, “polymy-
ositis”, “dermatomyositis”, “inclusion body myositis”, and “exercise”. Current literature
indicates that exercising has impact on both immune and non-­immune pathways in
patients with IIM. Exercise-­related benefits include (a) increased mitochondrial bio-
genesis/enzyme activity, (b) reconditioning of immune/inflammatory pathways, (c)
decreased endoplasmic reticulum stress, (d) modulation of gene expression, (e) in-
creased protein synthesis and cytoskeletal remodeling, and (f) decreased muscle fi-
brosis and non-­muscle area infiltrates. With its certain benefits, exercise stands as a
precious non-­pharmacological treatment option for patients with IIM.

KEYWORDS

aerobic exercise, exercise, idiopathic inflammatory myopathy, myositis, resistance training

1 | I NTRO D U C TI O N
The term idiopathic inflammatory myopathy (IIM) represents a het-
erogeneous group of diseases such as polymyositis, dermatomyo-
sitis, and inclusion body myositis. The incidence of inflammatory
myopathies is estimated at 7.98 cases/million/year, whereas the
prevalence is 14.0 cases per 100 000 inhabitants. Although inflam-
matory myopathy is a rare clinical condition, a systematic review by
Meyer et al revealed the increase in its frequency over time,1 possi-
bly as the result of earlier recognition and diagnosis.
The IIMs are characterized by muscle inflammation, and con-
sequent fibrosis. Although severe muscle weakness is the prom-
inent symptom, patients may also present with extra-­
muscular
manifestations including interstitial lung disease, skin rashes, and
arthritis. Management of myositis is often challenging and in-
volves a multitude of immunomodulatory and immunosuppressive
drugs. Glucocorticoids, the anchor agents of initial treatment, are
administered together with other immunosuppressants. 2 Non-­
pharmacological treatment strategies such as diet and exercise con-
stitute a vital part of management.3
Contrary to the previous concept of avoiding exercise in
IIM, exercising is now regarded as an essential and safe non-­
pharmacological supportive line of care in IIM.4,5 Studies have
mostly focused on the effects of exercise in patients with es-
tablished IIM. However, there is also evidence indicating that
an individualized and supervised home exercise program might

© 2021 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd

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896     
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 1756185x, 2021, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1756-185X.14104 by Universidade Do Estado Do Rio, Wiley Online Library on [01/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
COSKUN BENLIDAYI and GUPTA |
      897

be recommended in patients with recent-­onset IIM, with regu-

lar assessment and close monitoring of muscle performance and
health.4 Exercise provides both systemic and within-­m uscle adap-
tations. 6 Over the past decade, researchers have keenly explored
the immune-­m etabolic and physiological basis of improvement re-
lated to exercise in IIM. The present article aimed to review the
recent literature on exercising for IIM and to provide an insight
into the potential pathophysiological mechanisms underlying the
effectiveness of exercise in myositis.

2 |  S E A RC H M E TH O D O LO G Y

We systematically performed searches on PubMed/MEDLINE,

Scopus, Web of Science, and Google Scholar (first seven pages) using
the following keywords and their combinations: “idiopathic inflam-
matory myopathy”, “inflammatory myopathy”, “myositis”, “polymy-
ositis”, “dermatomyositis”, “inclusion body myositis”, and “exercise”.
Inclusion criteria were: (a) randomized controlled trials, (b) observa-
tional studies, (c) articles written in English language, and (d) articles
published during the last 7 years up to May 3, 2020. Exclusion cri-
teria were: (a) review articles, (b) study protocols, (c) pilot studies,
(d) case reports, (e) abstracts, and (f) studies addressing participants
<18 years of age. The search strategy was based on the recommen-
dations by Gasparyan et al.7 Figure 1 depicts the flowchart of the
narrative review.

3 |  PATH O PH YS I O LO G Y O F I D I O PATH I C

I N FL A M M ATO RY M YO PATH I E S

A close look at the pathophysiology of myositis would enhance our

understanding regarding the mechanisms underlying the beneficial
effects of exercising in patients with IIM. Both immune-­mediated
and non-­immune-­mediated pathways are important in the patho-
genesis of IIM.8 Recent insights into the molecular mechanisms
suggest varied pathogenic events in the different subtypes of IIM.
Although detailed discussion of each of these forms may be beyond
the scope of this review, we shall briefly touch upon the features
that are common across most phenotypes.
In most cases, an underlying genetic disposition catalyzes addi-
tive injury in the event of an environmental onslaught, such as viral
infections, drugs, smoking, or sunlight-­induced damage.9-­11 The an-
tigens released from damaged muscle, which is otherwise deemed
to be an immune-­privileged site, trigger a series of events, starting
with the activation of innate immune pathways, such as the Toll-­like
receptors (TLRs), and the release of pro-­inflammatory cytokines. The
muscle is unique in that these cytokines can result in an acute fiber F I G U R E 1   Flowchart of the review
dysfunction, manifesting as weakness disproportionate to the ev-
idence of systemic inflammation early in the course of the illness. Despite the fact that inflammatory myopathy is an immune-­
Later, these immune events trigger T-­cell-­mediated injury, antigen mediated disease much attention has been given to the role of
processing and presentation, germinal center formation, and autoan- non-­immune mechanisms of muscle dysfunction.12 It has been
tibody production for a sustained inflammatory response.9 shown in a major histocompatibility complex class I conditional

|
898       COSKUN BENLIDAYI and GUPTA
upregulation model in H+T+ mice that muscle weakness occurs
before inflammatory infiltrates are evident on muscle biopsy
specimens.13 Adenosine monophosphate deaminase-­
1 dysfunc-
tion, as a sign of cellular dysregulation, has been observed early
in the course of myositis in a mouse model.14 Nuclear magnetic
resonance spectroscopy can determine the concentrations of
phosphate metabolites and quantify muscle dysfunction, even in
clinically amyopathic cases.15 Established IIMs reveal fewer oxida-
tive slow-­t witch type I muscle fibers, 8 and the fast-­t witch type II A
muscle fibers, which predominantly utilize aerobic glycolytic me-
tabolism.16 Anaerobic switch of metabolism was identified in IIM.
Significantly increased lactate levels when compared with controls
indicate an impaired muscle oxidative efficiency in patients with
17
myositis. This, in part, explains the muscle endurance deficits
measured by the Myositis Functional Index-­2 in myositis patients
with normal or near-­n ormal strength in manual muscle testing.18
Recent literature suggests that one subset of IIM, inclusion body
myositis, may be reclassified as a mitochondrial disease,19 because
of the large body of evidence pointing towards the non-­immune-­
mediated pathways also being involved in the disease process of
IIM. 8,20-­22
Endoplasmic reticulum stress is another central event in the
pathogenesis of innate immune activation in IIM. Most evidence
centers around the activation of the nuclear factor-­
κB pathway
following the activation of TLRs in polymyositis and inclusion body
23
myositis subsets of IIM. Apart from the high mobility group box
chromosomal protein 1 (HMGB-­1), the muscle enzyme creatine ki-
nase, which is released as a result of muscle damage, also behaves as
an endogenous TLR ligand, accentuating the process. 24 Furthermore,
triggering of inflammasome-­
mediated inflammation produces a
surge of cytokines and protein synthesis, which results in an endo-
plasmic reticulum stress response. This culminates in further release
of heat-­shock proteins (particularly, hsp 70 and hsp 90 families) and
25
an endoplasmic reticulum overload response. The cells may even-
tually opt for autophagy to slow down and regulate the process or
undergo apoptosis. 26 A continued endoplasmic reticulum stress re-
sponse may lead to an unregulated surge of cytokines such as tumor
27
necrosis factor and interferons, which would directly inhibit fiber
function, and accentuate the TLR response resulting in a positive
feedback loop of inflammation. 23 The lack of protein homeostasis
goes one step further in inclusion body myositis, where inherent
defects in protein degradation pathways result in the accumulation
of degenerated protein such as the β-­amyloid fibrils, which further
11
weakens the degenerating and diseased muscle.
Another major component is oxidative-­stress-­induced muscle
damage, which further adds to the onslaught. 28 In the mitochondria,
reactive oxygen species are generated as a result of faulty function/
metabolism, compounding the deregulated cellular metabolism and
culminating in tissue damage from mitochondrial damage and sub-
22
sequent fiber atrophy. Both an excess activation of the endoplas-
mic reticulum response and deregulated mitochondrial function can
trigger caspases, leading to cellular apoptosis. As a result, mitochon-
drial dysfunction is the key event, with dominant hypoxia resulting
1756185x, 2021, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1756-185X.14104 by Universidade Do Estado Do Rio, Wiley Online Library on [01/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
in a chicken and egg situation of faulty metabolism and poor muscle
strength. Figure 2 depicts the pathophysiology of IIM.
4 | TH E M EC H A N I S M S O F E X E RC I S E-­
I N D U C E D B E N E FIT S I N I D I O PATH I C
I N FL A M M ATO RY M YO PATH I E S
The beneficial effects of exercise in IIM depend upon several mecha-
nisms (Figure 3). These include: (a) increased mitochondrial biogen-
esis/enzyme activity, (b) reconditioning of immune/inflammatory
pathways, (c) decreased endoplasmic reticulum stress, (d) modula-
tion of gene expression, (e) increased protein synthesis and cytoskel-
etal remodeling, and (f) decreased muscle fibrosis and non-­muscle
area infiltrates.
4.1 | Increased microcirculation and
mitochondrial function
Specific exercise types have distinct primary effects in muscles.
Strengthening exercises lead to larger improvements in muscle
strength, muscle power, and muscle hypertrophy, whereas endur-
ance exercises improve cardiovascular endurance. On the other
hand, these two exercise types may also interfere with each other.
Concurrent strengthening and endurance exercises optimize the
degree of muscle hypertrophy, strength, and endurance develop-
ment. 29,30 Both exercise types can increase capillary density and
thereby the microcirculation in muscles. Endurance exercises can
elevate mitochondrial enzyme activity.31 Resistance exercise was
shown to enhance mitochondrial function by improving mitochon-
drial quality control and mitochondrial oxidative capacity in a rat
model of sporadic inclusion body myositis.32 Boehler et al31 examined
the effects of endurance training (different protocols of cycling) on
microRNAs in myositis skeletal muscles in a sample of patients with
probable polymyositis and dermatomyositis. They used samples ob-
tained from patients participating in a controlled, randomized trial.33
Muscle biopsies were taken at baseline and after the finalization of
endurance training. The researchers compared the samples from pa-
tients and controls. They determined an increase in mitochondrial
proteins including adenylate kinase 3 and 3-­hydroxyisobutyrate de-
hydrogenase. In this regard, exercising may improve disease by in-
creasing mitochondrial biogenesis.31
4.2 | Immunomodulation
Physical activity also has immunomodulatory effects. It has been
shown that regular exercise training has the potential to induce im-
mune competence and to reduce the risk of infection.34 Prolonged
mechanical stress has the ability to modulate cell differentiation, as
well as local and systemic inflammatory responses.35 In an in vitro
study, mechanical stretch of myoblasts was shown to reduce the

COSKUN BENLIDAYI and GUPTA
F I G U R E 2   The pathophysiology of
idiopathic inflammatory myopathies.
AMPD1, adenosine monophosphate
deaminase-­1; ER, endoplasmic reticulum;
HSP, heat-­shock protein; NF-­κB, nuclear
factor-­κB; ROS, reactive oxygen species;
TLR, toll-­like receptor
expression of muscle autoantigens and of pro-­inflammatory TLR3.36
Hence, exercise provides some anti-­inflammatory effects, as well.37
Reduction in systemic inflammation and disease activity is partly
achieved by the decreased expression of pro-­
inflammatory and
pro-­fibrotic genes.38 A trial in patients with sporadic inclusion body
myositis examined the effects of 12 weeks of low-­load blood-­flow
restriction exercise on immune and inflammatory responses.39 The
protocol comprised unilateral leg press, knee extension, knee flexion
(introduced from the 4th week), calf raise, and dorsiflexion.40 Muscle
biopsies from tibialis anterior/vastus lateralis revealed an increase
in myocellular infiltration of CD3− CD8+-­expressing natural killer
cells following blood-­flow restriction exercise, which is consistent
with an amplified immune response. On the other hand, no changes
were demonstrated in terms of cytotoxic T cells (CD3+ CD8+,
CD3+ CD28−), regulatory T cells (FOXP3+) or macrophage infil-
trates. Qualitative analysis revealed that the spatial positioning of
+ +
M2 anti-­inflammatory (CD68  CD206 ) macrophages was altered,
these cells appeared to co-­localize more closely to small-­sized (pos-
sibly atrophied) type 2 fibers.39 This finding contradicts the previous
concept that exercising has a detrimental effect on the immunologi-
cal muscle in patients with myositis. The results support the notion
that low-­load exercise has no risk of intensified inflammatory activ-
ity.39 Low-­load blood-­flow restriction exercise might be beneficial
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|
      899
in preventing/delaying myositis-­related decline in muscle contractile
capacity without imposing a high magnitude of mechanical strain on
muscles and with no exacerbation of the disease.40,41 The potential
mechanisms underlying this positive effect of low-­load blood-­flow
restriction exercise include boosted muscle fiber recruitment, over-
production of hormones, and increased muscle protein synthesis as
a response to diminished blood flow.41
4.3 | Decreased muscle fibrosis and
modulation of authophagy
Chronic inflammation leads to muscle fibrosis in patients with IIM.
Exercising can also be effective in decreasing muscle fibrosis and
non-­muscle area infiltrates.38 The autophagy-­lysosome system is an
important pathway in the pathogenesis of IIM. Jeong et al,42 in a
sporadic inclusion body myositis animal model, showed that resistive
exercise modulates autophagy. Decreased muscle fibrosis and mod-
ulation of autophagy could be one of the potential reasons for sus-
tained muscle strength improvement after an exercise intervention.
A multicenter randomized controlled study with a 1-­year open exten-
sion follow up examined the long-­term effects of exercise interven-
tion in patients with established polymyositis and dermatomyositis.
 1756185x, 2021, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1756-185X.14104 by Universidade Do Estado Do Rio, Wiley Online Library on [01/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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900       COSKUN BENLIDAYI and GUPTA

F I G U R E 3   The underlying mechanisms of exercise-­related benefits in idiopathic inflammatory myopathies (IIMs) (illustrated by the
author ICB); ER, endoplasmic reticulum. Exercise induces mitochondrial biosynthesis, thereby aerobic metabolism. This adaptation improves
endurance in patients with IIM. Exercise can modulate gene expression in muscle tissue. Upregulation of genes related to structural proteins
induces cytoskeletal growth. Increased capillary formation improves tissue oxygenation and aerobic metabolism. Exercising can also inhibit
the synthesis of pro-­inflammatory cytokines and provides anti-­inflammatory effects related to decreased disease activity. Endoplasmic
reticulum stress can be decreased by exercise. This adaptation further modulates pro-­inflammatory cytokine synthesis and autophagy

The protocol included cycling at 70% of Vo2max, muscular endur-
ance exercise of the knee extensors at 30%-­4 0% of one voluntary
repetition maximum. The results showed that improvement in five
voluntary repetition maximum sustained up to 52 weeks compared
with baseline indicating the sustained muscle strength up to 1 year
after a supervised exercise program in patients with IIM.43
endurance exercise regimen in patients with IIM.8,33 Aerobic training
such as cycling would be the treatment of choice to improve endur-
ance in patients with IIM.33
4.5 | Modulation of mRNAs

MicroRNAs are regulators of gene expression. They play a role in

4.4 | Angiogenesis
Due to thickened endothelial cells and reduced number of capillar-
8
ies, deterioration in oxygen transport occurs in IIM. A sub-­study
of a randomized controlled trial among patients with IIM revealed
that an endurance exercise program upregulated genes related to
mitochondrial biogenesis, protein synthesis, and cytoskeletal re-
modeling. Exercise made the largest fold change in genes related
to capillary growth (Fms-­related tyrosine kinase 3 ligand [FLT3L]).
Endurance exercises, thereby, have the capacity to induce growth
of capillaries/angiogenesis, increase mitochondrial enzyme activ-
ity, modulate mitochondrial pathways including oxidative phospho-
rylation, and enhance aerobic capacity. Polypeptides belonging to
the cytochrome c oxidase family in complex IV in mitochondria are
highly affected by exercise. On the other hand, proteins involved
in the glycolysis pathway are downregulated in exercised patients,
indicating the reduced production of energy by anaerobic glycoly-
sis.8 These changes, overall, may explain the improvement in Vo2max
and the decrease in extracellular lactate concentrations following an
several inflammatory rheumatic diseases. As regulators of myogenic
differentiation and maintenance, the dysregulated expression of mi-
croRNAs is also important for the pathogenesis of IIM. Increased re-
lease of pro-­inflammatory cytokines in IIM, which is partially driven
by the activation of nuclear factor-­κB, can suppress the expression
of microRNAs.31 Boehler et al31 found that a 1 hour endurance exer-
cise training program three times a week for 12 weeks enhanced the
expression of microRNAs that modulate mRNA transcripts playing
a role in suppressing inflammation, improving aerobic activity and
inducing muscle growth. Exercise-­induced microRNAs downregu-
late transcripts taking part in immune pathways, glycolytic metab-
olism, and muscle atrophy. MicroRNAs can affect gene expression
through translational regression and/or transcriptional regulation.
Exercise can alter the expression of proteins (adenylate kinase 3 and
3-­hydroxyisobutyrate dehydrogenase) that are located in the mito-
chondria and involved in aerobic respiration. It is also possible that
regular exercising increases Apurinic/Apyrimidinic Endonuclease 1
(APEX1) which can relieve oxidative stress in skeletal muscle during
an acute bout of exercise. This is particularly important when the

COSKUN BENLIDAYI and GUPTA
reduced oxidative muscle efficiency and the precocious resort to an-
aerobic activity in patients with IIM are considered. Overall, exercise
can improve disease phenotype by modulating microRNAs, either at
31
the transcript level or by translational regulation.
4.6 | Decreased endoplasmic reticulum stress
Pathological endoplasmic reticulum stress in skeletal muscles of
patients with IIM enhances the inflammatory and autoimmune re-
sponse, leading to muscle weakness and fiber damage.44,45 The
pathology is characterized by inflammation and skeletal muscle
damage (central nucleation, variation in fiber size, fibrosis, and fiber
31
atrophy). Endurance exercises have the potential to downregulate
the genes related to endoplasmic reticulum stress. Decrease in en-
doplasmic reticulum stress leads to the deactivation of downstream
ubiquitin proteasome pathways and protects from muscle degenera-
tion. It may also inhibit tumor necrosis factor expression in skeletal
muscles.8
4.7 | Decreased production of reactive
oxygen species
Patients with IIM have almost 25% lower Vo2max and 35% lower
33
power output than the healthy population. Mitochondrial dys-
functions in IIM contribute to poor aerobic respiration and exercise
capacity. Mitochondrial malfunction is partly mediated by interferon-­
β-­induced reactive oxygen species in patients with myositis. On the
other hand, mitochondrial malfunction, itself, increases the produc-
tion of reactive oxygen species, which play role in type I interferon-­
inducible gene expression and muscle inflammation. 28 Exercising has
the potential to modulate this cross-­t alk among immunity, mitochon-
drial dysfunction, and over-­production of reactive oxygen species,
partly through its interaction with the processes occurring in the
mitochondria. Munters et al8 found that aerobic exercise in patients
with established polymyositis and dermatomyositis can induce an
aerobic phenotype and inhibit the inflammatory response in muscle
fibers. A study by de Souza et al addressed the feasibility, safety,
and efficacy of exercise training in sedentary patients with immune-­
mediated necrotizing myopathies. As a potential coadjuvant therapy,
supervised exercise training increased aerobic capacity, muscle
strength, and function, with no impairment in disease status.46
4.8 | Upregulated oxidative phosphorylation
Exercising can improve the ability of the electron transport chain to
generate the proton gradient required for ATP production. Following
an endurance exercise regimen, substantial increase is observed in
several cytochrome c oxidase subunits/enzymes (especially the c ox-
idase subunit 2) involved in electron transportation.8 Exercise leads
to preferential production of energy by oxidative phosphorylation
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|
      901
instead of by glycolysis, thereby causing a shift to aerobic metabo-
lism, which increases muscle resistance to fatigue in patients with
IIM.8 Overall, exercise can improve oxygen uptake, muscle strength,
muscle functional capacity, clinical state, and general well-­being in
this particular patient group.43,47
There are several limitations to be discussed. The studies in-
cluded in this review mostly focused on the effects of exercise in
patients with established IIM. However, there is also evidence re-
garding the effects of exercise training in patients with early active
myositis. It should also be noted that, most of the studies included in
the current review have small sample sizes. Additionally, some pop-
ulations are homogeneous and there may be difficulty in applying
their findings to other populations.
5 | CO N C LU D I N G R E M A R K S
Current evidence confirms the benefits of exercising in patients
with IIM. The benefits are related to immune/inflammatory path-
ways, modulation of gene expression/protein synthesis, decreased
endoplasmic reticulum stress, increased capillary growth, and mito-
chondrial enzyme activity. Exercising can increase muscle strength
and endurance, decrease disease activity and disability, and improve
quality of life in patients with myositis. It is of great importance to
implement exercise in management protocols of patients with IIM.
AC K N OW L E D G M E N T S
None to report.
C O N FL I C T S O F I N T E R E S T
The authors declare that they have no conflicts of interest.
E T H I C A L A P P R OVA L
This article does not contain any studies with human participants or
animals performed by the authors.
ORCID
Ilke Coskun Benlidayi  https://orcid.org/0000-0001-6517-5969
Latika Gupta  https://orcid.org/0000-0003-2753-2990
REFERENCES
1. Meyer A, Meyer N, Schaeffer M, Gottenberg JE, Geny B, Sibilia J.
Incidence and prevalence of inflammatory myopathies: a system-
atic review. Rheumatology (Oxford). 2015;54(1):50-­63. https://doi.
org/10.1093/rheum​atolo​g y/keu289
2. Oddis CV, Aggarwal R. Treatment in myositis. Nat Rev Rheumatol.
2018;14(5):279-­289. https://doi.org/10.1038/nrrhe​um.2018.42
3. Barsotti S, Lundberg IE. Current treatment for myositis. Curr Treatm
Opt Rheumatol. 2018;4(4):299-­315. https://doi.org/10.1007/s4067​
4- ­018- ­0106-­2
4. Alexanderson H, Munters LA, Dastmalchi M, et al. Resistive home
exercise in patients with recent-­ onset polymyositis and derma-
tomyositis –­a randomized controlled single-­blinded study with a
2-­year followup. J Rheumatol. 2014;41(6):1124-­ 1132. https://doi.
org/10.3899/jrheum.131145

|
902       COSKUN BENLIDAYI and GUPTA
5. Mattar MA, Gualano B, Roschel H, et al. Exercise as an adjuvant
treatment in persistent active polymyositis. J Clin Rheumatol.
2014;20(1):11-­15. https://doi.org/10.1097/RHU.00000​0 0000​
000056
6. Alemo Munters L, Alexanderson H, Crofford LJ, Lundberg IE.
New insights into the benefits of exercise for muscle health in pa-
tients with idiopathic inflammatory myositis. Curr Rheumatol Rep.
2014;16(7):429. https://doi.org/10.1007/s1192​6- ­014- ­0 429-­4
7. Gasparyan AY, Ayvazyan L, Blackmore H, Kitas GD. Writing a nar-
rative biomedical review: considerations for authors, peer review-
ers, and editors. Rheumatol Int. 2011;31:1409-­ 1417. https://doi.
org/10.1007/s0029​6-­011-­1999-­3
8. Munters LA, Loell I, Ossipova E, et al. Endurance exercise im-
proves molecular pathways of aerobic metabolism in patients with
myositis. Arthritis Rheumatol. 2016;68(7):1738-­ 1750. https://doi.
org/10.1002/art.39624
9. Dunga SK, Sundaram TG, Kavadichanda CG. Pathogenesis of
muscle weakness in inflammatory myositis. Indian J Rheumatol.
2020;15(6):99. https://doi.org/10.4103/injr.injr_120_20
10. Rider LG, Wu L, Mamyrova G, Targoff IN, Miller FW. Childhood
Myositis Heterogeneity Collaborative Study Group. Environmental
factors preceding illness onset differ in phenotypes of the juve-
nile idiopathic inflammatory myopathies. Rheumatology (Oxford).
2010;49(12):2381-­2390. https://doi.org/10.1093/rheum​atolo​g y/
keq277
11. Miller FW, Lamb JA, Schmidt J, Nagaraju K. Risk factors and disease
mechanisms in myositis. Nat Rev Rheumatol. 2018;14(5):255-­268.
https://doi.org/10.1038/nrrhe​um.2018.48
12. Coley W, Rayavarapu S, Nagaraju K. Role of non-­immune mech-
anisms of muscle damage in idiopathic inflammatory myopathies.
Arthritis Res Ther. 2012;14(2):209. https://doi.org/10.1186/ar3791
13. Nagaraju K, Raben N, Loeffler L, et al. Conditional up-­regulation
of MHC class I in skeletal muscle leads to self-­sustaining autoim-
mune myositis and myositis-­ specific autoantibodies. Proc Natl
Acad Sci USA. 2000;97(16):9209-­ 9214. https://doi.org/10.1073/
pnas.97.16.9209
14. Coley W, Rayavarapu S, Pandey GS, et al. The molecular basis of
skeletal muscle weakness in a mouse model of inflammatory my-
opathy. Arthritis Rheum. 2012;64(11):3750-­ 3759. https://doi.
org/10.1002/art.34625
15. Park JH, Olsen NJ, King L Jr, et al. Use of magnetic resonance imag-
ing and p-­31 magnetic resonance spectroscopy to detect and quan-
tify muscle dysfunction in the amyopathic and myopathic variants
of dermatomyositis. Arthritis Rheum. 1995;38(1):68-­77.
16. Loell I, Helmers SB, Dastmalchi M, et al. Higher proportion of fast-­
twitch (type II) muscle fibres in idiopathic inflammatory myop-
athies -­evident in chronic but not in untreated newly diagnosed
patients. Clin Physiol Funct Imaging. 2011;31(1):18-­25. https://doi.
org/10.1111/j.1475-­097X.2010.00973.x
17. Bertolucci F, Neri R, Dalise S, Venturi M, Rossi B, Chisari C.
Abnormal lactate levels in patients with polymyositis and dermato-
myositis: the benefits of a specific rehabilitative program. Eur J Phys
Rehabil Med. 2014;50(2):161-­169.
18. Amici DR, Pinal-­Fernandez I, Pagkatipunan R, et al. Muscle en-
durance deficits in myositis patients despite normal manual mus-
cle testing scores. Muscle Nerve. 2019;59(1):70-­ 75. https://doi.
org/10.1002/mus.26307
19. De Paepe B. Sporadic inclusion body myositis: an acquired mito-
chondrial disease with extras. Biomolecules. 2019;9(1):15. https://
doi.org/10.3390/biom9​010015
20. Catalán-­García M, Garrabou G, Morén C, et al. Mitochondrial DNA
disturbances and deregulated expression of oxidative phosphor-
ylation and mitochondrial fusion proteins in sporadic inclusion
body myositis. Clin Sci (Lond). 2016;130(19):1741-­1751. https://doi.
org/10.1042/CS201​60080
1756185x, 2021, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1756-185X.14104 by Universidade Do Estado Do Rio, Wiley Online Library on [01/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
21. Rygiel KA, Tuppen HA, Grady JP, et al. Complex mitochondrial DNA
rearrangements in individual cells from patients with sporadic in-
clusion body myositis. Nucleic Acids Res. 2016;44(11):5313-­5329.
https://doi.org/10.1093/nar/gkw382
22. Lightfoot AP, Nagaraju K, McArdle A, Cooper RG. Understanding
the origin of non-­immune cell-­mediated weakness in the idiopathic
inflammatory myopathies -­potential role of ER stress pathways.
Curr Opin Rheumatol. 2015;27(6):580-­585. https://doi.org/10.1097/
BOR.00000​0 0000​0 00212
23. Brunn A, Zornbach K, Hans VH, Haupt WF, Deckert M. Toll-­like
receptors promote inflammation in idiopathic inflammatory myop-
athies. J Neuropathol Exp Neurol. 2012;71(10):855-­867. https://doi.
org/10.1097/NEN.0b013​e3182​6bf7f3
24. Ulfgren AK, Grundtman C, Borg K, et al. Down-­regulation of the ab-
errant expression of the inflammation mediator high mobility group
box chromosomal protein 1 in muscle tissue of patients with poly-
myositis and dermatomyositis treated with corticosteroids. Arthritis
Rheum. 2004;50(5):1586-­1594.
25. Rayavarapu S, Coley W, Van der Meulen JH, et al. Activation of
the ubiquitin proteasome pathway in a mouse model of inflam-
matory myopathy: a potential therapeutic target. Arthritis Rheum.
2013;65(12):3248-­3258. https://doi.org/10.1002/art.38180
26. Vattemi G, Engel WK, McFerrin J, Askanas V. Endoplasmic reticu-
lum stress and unfolded protein response in inclusion body myosi-
tis muscle. Am J Pathol. 2004;164(1):1-­7. https://doi.org/10.1016/
S0002​-­9440(10)63089​-­1
27. Nagaraju K, Casciola-­Rosen L, Lundberg I, et al. Activation of the
endoplasmic reticulum stress response in autoimmune myositis: po-
tential role in muscle fiber damage and dysfunction. Arthritis Rheum.
2005;52(6):1824-­1835. https://doi.org/10.1002/art.21103
28. Meyer A, Laverny G, Allenbach Y, et al. IFN-­β-­induced reactive ox-
ygen species and mitochondrial damage contribute to muscle im-
pairment and inflammation maintenance in dermatomyositis. Acta
Neuropathol. 2017;134(4):655-­666. https://doi.org/10.1007/s0040​
1-­017-­1731-­9
29. Gäbler M, Prieske O, Hortobágyi T, Granacher U. The effects of
concurrent strength and endurance training on physical fitness
and athletic performance in youth: a systematic review and meta-­
analysis. Front Physiol. 2018;9:1057. https://doi.org/10.3389/
fphys.2018.01057
3 0. Mikkola J, Rusko H, Izquierdo M, Gorostiaga EM, Häkkinen K.
Neuromuscular and cardiovascular adaptations during concurrent
strength and endurance training in untrained men. Int J Sports Med.
2012;33(9):702-­710. https://doi.org/10.1055/s-­0 031-­1295475
31. Boehler JF, Hogarth MW, Barberio MD, et al. Effect of endurance
exercise on microRNAs in myositis skeletal muscle-­A randomized
controlled study. PLoS ONE. 2017;12(8):e0183292. https://doi.
org/10.1371/journ​al.pone.0183292
32. Koo JH, Kang EB, Cho JY. Resistance exercise improves mito-
chondrial quality control in a rat model of sporadic inclusion
body myositis. Gerontology. 2019;65(3):240-­ 252. https://doi.
org/10.1159/00049​4723
33. Alemo Munters L, Dastmalchi M, Katz A, et al. Improved exer-
cise performance and increased aerobic capacity after endurance
training of patients with stable polymyositis and dermatomyositis.
Arthritis Res Ther. 2013;15(4):R83. https://doi.org/10.1186/ar4263
3 4. Krüger K, Mooren FC, Pilat C. The immunomodulatory effects of
physical activity. Curr Pharm Des. 2016;22(24):3730-­3748. https://
doi.org/10.2174/13816​12822​66616​03221​45107
35. Tiffreau V, Rannou F, Kopciuch F, et al. Postrehabilitation func-
tional improvements in patients with inflammatory myopathies:
the results of a randomized controlled trial. Arch Phys Med Rehabil.
2017;98(2):227-­234. https://doi.org/10.1016/j.apmr.2016.09.125
36. Chen R, Feng L, Ruan M, Liu X, Adriouch S, Liao H. Mechanical-­
stretch of C2C12 myoblasts inhibits expression of toll-­like receptor

COSKUN BENLIDAYI and GUPTA
3 (TLR3) and of autoantigens associated with inflammatory myopa-
thies. PLoS ONE. 2013;8(11):e79930. https://doi.org/10.1371/journ​
al.pone.0079930
37. Gleeson M, Bishop NC, Stensel DJ, Lindley MR, Mastana SS, Nimmo
MA. The anti-­inflammatory effects of exercise: mechanisms and
implications for the prevention and treatment of disease. Nat Rev
Immunol. 2011;11:607-­615.
38. Nader GA, Dastmalchi M, Alexanderson H, et al. A longitudinal,
integrated, clinical, histological and mRNA profiling study of resis-
tance exercise in myositis. Mol Med. 2010;16:455-­464.
39. Jensen KY, Jacobsen M, Schrøder HD, et al. The immune system
in sporadic inclusion body myositis patients is not compromised
by blood-­ flow restricted exercise training. Arthritis Res Ther.
2019;21(1):293. https://doi.org/10.1186/s1307​5-­019-­2036-­2
4 0. Jørgensen SL, Bohn MB, Aagaard P, Mechlenburg I. Efficacy of
low-­load blood flow restricted resistance EXercise in patients
with Knee osteoarthritis scheduled for total knee replacement
(EXKnee): protocol for a multicentre randomised controlled trial.
BMJ Open. 2020;10(10):e034376. https://doi.org/10.1136/bmjop​
en-­2019-­034376
41. Mattar MA, Gualano B, Perandini LA, et al. Safety and possible
effects of low-­ intensity resistance training associated with par-
tial blood flow restriction in polymyositis and dermatomyositis.
Arthritis Res Ther. 2014;16(5):473. https://doi.org/10.1186/s1307​
5-­014-­0 473-­5
42. Jeong JH, Yang DS, Koo JH, Hwang DJ, Cho JY, Kang EB. Effect
of Resistance Exercise on Muscle Metabolism and Autophagy in
sIBM. Med Sci Sports Exerc. 2017;49(8):1562-­ 1571. https://doi.
org/10.1249/MSS.00000​0 0000​0 01286
1756185x, 2021, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1756-185X.14104 by Universidade Do Estado Do Rio, Wiley Online Library on [01/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
|
      903
43. Alemo Munters L, Dastmalchi M, Andgren V, et al. Improvement in
health and possible reduction in disease activity using endurance
exercise in patients with established polymyositis and dermatomy-
ositis: a multicenter randomized controlled trial with a 1-­year open
extension followup. Arthritis Care Res (Hoboken). 2013;65(12):1959-­
1968. https://doi.org/10.1002/acr.22068
4 4. Rayavarapu S, Coley W, Nagaraju K. Endoplasmic reticulum stress
in skeletal muscle homeostasis and disease. Curr Rheuma-­tol Rep.
2012;14:238-­243.
45. Zong M, Lundberg IE. Pathogenesis, classification and treat-­ment
of inflammatory myopathies. Nat Rev Rheumatol. 2011;7:297-­3 06.
46. de Souza JM, de Oliveira DS, Perin LA, et al. Feasibility, safety and
efficacy of exercise training in immune-­mediated necrotising myop-
athies: a quasi-­experimental prospective study. Clin Exp Rheumatol.
2019;37(2):235-­241.
47. Wiesinger GF, Quittan M, Aringer M, et al. Improvement of phys-
ical fitness and muscle strength in polymyositis/dermatomyositis
patients by a training programme. Br J Rheumatol. 1998;37(2):196-­
200. https://doi.org/10.1093/rheum​atolo​g y/37.2.196
How to cite this article: Coskun Benlidayi I, Gupta L. The
pathophysiological effects of exercise in the management of
idiopathic inflammatory myopathies: A scoping review. Int J
Rheum Dis. 2021;24:896–­903. https://doi.org/10.1111/1756-­
185X.14104