Ageing Research Reviews 64 (2020) 101185

Contents lists available at ScienceDirect

Ageing Research Reviews

journal homepage: www.elsevier.com/locate/arr

Markers of inflammation and their association with muscle strength and

mass: A systematic review and meta-analysis
Camilla S.L. Tuttle a, Lachlan A.N. Thang a, Andrea B. Maier a, b, *
a
Department of Medicine and Aged Care, @AgeMelbourne, The Royal Melbourne Hospital, The University of Melbourne, Victoria, Australia
b
Department of Human Movement Sciences, @AgeMelbourne, Faculty of Behavioural and Movement Sciences, Amsterdam Movement Sciences, Vrije Universiteit,
Amsterdam, the Netherlands

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Chronic inflammation has been associated with sarcopenia and its components skeletal muscle
Cytokines strength and muscle mass. The aim of this systematic review and meta-analysis was to determine the relationship
C-reactive protein between systemic inflammation, muscle strength and/or muscle mass in adults.
Inflammation
Methods: An electronic search using keywords such as ‘acute phase proteins, cytokines and sarcopenia, muscle
Interleukin-6
Muscle strength
mass, muscle strength’ was conducted via Pubmed, Web of Science and Embase from inception until the 30th of
Muscle mass June 2020. A meta-analysis using correlation data was performed to determine the overall relationship between
Muscle atrophy inflammation and muscle strength and muscle mass in adults.
Sarcopenia Results: Overall, 168 articles; 149 cross-sectional articles (n = 76,899 participants, 47.0 % male) and 19 longi­
tudinal articles (n = 12,295 participants, 31.9 % male) met inclusion criteria. Independent of disease state,
higher levels of C reactive protein (CRP), Interleukin (IL)-6 and Tumor necrosis factor (TNF)α were associated
with lower handgrip and knee extension strength (CRP; r = − 0.10, p < 0.001, IL-6; r = − 0.13, p < 0.001, TNFα; r
= − 0.08, p < 0.001 and CRP; r = − 0.18, p < 0.001, IL-6; r = − 0.11, p < 0.001, TNFα; r = − 0.13, p < 0.001
respectively) and muscle mass (CRP; r = − 0.12, p < 0.001, IL-6; r = − 0.09, p < 0.001, TNFα; r = − 0.15, p <
0.001). Furthermore, higher levels of systemic inflammatory markers appeared to be associated with lower
muscle strength and muscle mass over time.
Conclusion: Higher levels of circulating inflammatory markers are significantly associated with lower skeletal
muscle strength and muscle mass.

1. Introduction (Cruz-Jentoft et al., 2019). However, a common feature underlying both

Skeletal muscle plays an integral role in maintaining homeostasis
across organ systems. Skeletal muscle is plastic, changing dynamically in
response to physical activity, load, injury, illness and ageing (Haddad
et al., 2005). The age-related loss of skeletal muscle strength, muscle
mass and physical performance (sarcopenia), has been associated with
falls and fractures in older populations (Yeung et al., 2019a), and re­
mains a largely undiagnosed condition (Fielding et al., 2011; Reijnierse
et al., 2017; Yeung et al., 2019b). Beyond ageing, sarcopenia is associ­
ated with age-related diseases such as dementia, chronic obstructive
pulmonary disease and cardiovascular disease (Pacifico et al., 2020). In
older adults, several of these diseases coincide with decline in muscle
mass and whether this is caused by ageing or disease is largely unknown
conditions is inflammation (Chhetri et al., 2018; Chung et al., 2019;
Souza et al., 2017).
Chronic inflammation, characterised by higher systemic cytokine
and acute phase protein circulation (Ferrucci et al., 2005; Pedersen
et al., 2003), is not only linked to ageing ‘inflammaging’ (Franceschi
et al., 2000) but also muscle mass loss (Ali and Garcia, 2014). Tumor
necrosis factor α (TNFα) released from diseased tissues has been shown
to exert endocrine effects on skeletal muscle (Powers et al., 2016).
In vitro studies have shown that TNFα is a key endocrine stimulus for
contractile dysfunction in chronic inflammation and that the muscle
derived reactive oxygen species (ROS) and nitric oxide (NO) participate
in depressing specific force of muscle fibre, which can lead to muscle
atrophy (Li et al., 2000). Furthermore Interleukin (IL)-6, a key cytokine

* Corresponding author at: Age, Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, VU University Amsterdam, Amsterdam
Movement Sciences, van der Boechorststraat 7, 1081 BT, Amsterdam, the Netherlands.
E-mail address: a.b.maier@vu.nl (A.B. Maier).

https://doi.org/10.1016/j.arr.2020.101185
Received 30 April 2020; Received in revised form 30 August 2020; Accepted 15 September 2020
Available online 26 September 2020
1568-1637/© 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
C.S.L. Tuttle et al. Ageing Research Reviews 64 (2020) 101185

involved in low-grade chronic inflammation, has been shown to facili­ Table 1.

tate muscle atrophy via blunting muscle anabolism and energy ho­
meostasis (Haddad et al., 2005). However, despite significant research
within the area the extent of the association between systemic markers
of inflammation such as, TNFα, IL-6 and clinical markers of skeletal
muscle strength and muscle mass is unknown, particularly in pop­
ulations with age-related diseases (Can et al., 2017; Kwak et al., 2018).
A systematic review and meta-analysis of the literature was under­
taken to identify if systemic inflammatory markers are associated with
lower skeletal muscle strength and muscle mass in adults sub grouped by
inflammatory marker, population and sex.
2. Methods
2.1. Search strategy
This systematic review was conducted following the guidelines of the
Preferred Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) statement (Liberati et al., 2009). The systematic search of
the literature was conducted using the electronic databases: PubMed,
EMBASE and Web of Science from inception until 30/06/2020. The
search included search terms relating to inflammatory markers (“cyto­
kines”, “acute phase proteins”) and muscle measures (“sarcopenia”,
“muscle mass”, “muscle strength”, “hand strength”). The complete
search strategy for this systematic review can be found in Supplementary
Table 1
Overview of the included articles stratified by population muscle, strength and
muscle mass.
Cross-sectional articles (N = Longitudinal articles (N =
149) 19)
Articles Sample %M Articles Sample
2.2. Study selection
Publications returned from the databases were imported into
Endnote, and duplicates removed. Titles and abstracts of selected arti­
cles were screened by two independent reviewers (LT, JK or CT) using
Covidence software (Covidence systematic review software, Veritas Health
Innovation, Melbourne, Australia). Articles were included if 1) study
cohort mean or median age was ≥18 years, 2) data for at least one in­
flammatory marker was available, and 3) data for at least one muscle
measure of either muscle strength or muscle mass was available. Studies
were excluded if 1) in vitro or animal models were utilised; 2) partici­
pants had a genetic disease, such as progeroid disease or muscular
dystrophies; 3) article not written in English and 4) conference abstracts,
reviews, editorials, letter to the editor and case reports. Two indepen­
dent reviewers (LT, JK or CT) screened the full-text articles using the
above criteria and the additional criteria; 5) no statistical test assessing
an association between inflammatory markers and muscle strength and/
or muscle mass was used. Disagreement of the eligibility of an article
was resolved by the involvement of a third reviewer (CT).
2.3. Data extraction
Data extraction was performed by two independent reviewers (CT,
LT). The following data were extracted: author, year of publication,
study design (cross-sectional (C), longitudinal (L)), study population,
time to follow up (L studies), sample size, age of participants, percentage
of males, health status, inflammatory marker, muscle parameter and
technique used to measure muscle strength or muscle mass.
2.4. Statistical analysis
%M

Total Population 149 76,899 470 19 12,295 31.9 The meta-analysis was performed using Comprehensive Meta-
Cancer 9 1370 52.0 1 79 58 Analysis (CMA) Software (Version 3.0, Biostat, Englewood, New Jersey,
Cardiovascular 12 2307 55.4 0 0 0
USA). To determine the overall association between inflammatory
Community Dwelling 41 49,937 46.3 9 11,214 31.4
Depression 3 1111 34.2 0 0 0 marker and muscle mass and strength, data extracted from articles was
Metabolic 8 1703 68.1 0 0 0 entered using one of two formats. Where the article provided a corre­
Frail 1 130 67.5 0 0 0 lation coefficient (r) for inflammatory marker and muscle parameter; r,
Geriatric 11 2343 22.9 1 0 0 sample size and direction of the association was used, when r was not
GIT 5 471 59.9 0 0 0
Healthy 7 1923 69.6 5 668 30.8
provided, but the sample size, p value and the direction of the associa­
Immune 6 4252 50.6 0 0 0 tion was given, r was calculated. Z-scores were calculated from the
Inpatients 3 792 44.8 0 0 0 correlation coefficients using Fisher’s method and pooled under a
Low Back Pain 1 1078 83.0 0 0 0 random effects model. This method was used to reduce the risk of un­
Medullar Lumbar 1 20 100 0 0 0
known factors responsible for variability even under homogeneity.
Multimorbid 1 542 51.0 0 0 0
Osteoarthritis 4 454 31.4 1 186 32 Heterogeneity of the results was investigated using the I-squared test. In
Post Menopause 3 86 0 1 43 0 addition to the overall analysis, the meta-analysis was sub grouped by
Post-Polio 0 0 0 1 49 36 inflammatory marker, population and sex. Begg’s funnel plot and Eggers
Renal Disease 15 2260 60.4 0 0 0 Regression intercept were used to determine publication bias.
Respiratory Disease 14 3541 56.9 0 0 0
Rheumatoid Arthritis 5 385 26.5 0 0 0
Sarcopenia 0 0 0 1 56 42.9 3. Results
Muscle Strength (MS) 121 70,647 47.3 15 12,062 32.7
HGS 90 66,212 46.4 9 10,536 43.7 3.1. Article demographics
Knee extension 32 8807 51.1 8 3596 27.3
Knee flexion 5 436 36.9 0 0 0
Rep-Max strength 3 224 50.4 0 0 0 Fig. 1 illustrates the overall search strategy. The final search
Other 4 1393 67.2 0 0 0 retrieved 8877 articles. After exclusion of duplicates 5817 articles were
Muscle Mass (MM) 82 19,812 52.4 9 3394 28.6 screened for title and abstract of which 845 were screened for full text.
BIA# 23 3901 61.9 2 135 50.5 Overall 168 articles were included in this systematic review. Table 1
DEXA 35 9793 48.0 6 3268 25.7
CT 17 6172 57.1 1 1970 53.0
provides a comprehensive overview of included articles, categorized by
MRI 3 92 69.5 0 0 0 the study design; C = 149 and L = 19 articles. For a detailed description
Other 9 1091 58.8 0 0 0 of each article included in this review refer to Supplementary Table 2. The
Abbreviations – BIABioimpedance analysis, CT Computed Tomography, DEXA total number of included participants for cross-sectional studies was
Dual-energy x-ray absorptiometry, HGS Handgrip strength, MRI Magnetic 76,899 of which 47.0 % were male. Conversely, 12,295 participants,
resonance imaging, Other MS; Hip strength, Repetition Max, Shoulder strength, 31.9 % male, have been included in longitudinal studies; with follow-up
Strength score,Other MM; Anthropometry, Creatinine Kinase, 40K LBM, #In­ ranging from 1 month to 16 years. Overall, community dwelling cohorts
cludes - Tanita digital scale. assessing the association between systemic inflammation and muscle

2
C.S.L. Tuttle et al.
Fig. 1. Overview of search strategy.
strength and/or muscle mass were reported most frequently (C = 41/
149, L = 9/19 articles).
The association between inflammation and muscle strength and/or
muscle mass have been assessed with 31 acute phase proteins and cy­
tokines (Table 2). Muscle strength was reported more frequently than
muscle mass (C = 121/149 vs. 82/149; L = 15/19 vs. 9/19 articles
respectively). Handgrip strength was the most frequently used measure
(C = 90/149, L = 9/19 articles) to determine muscle strength. To
determine muscle mass, dual-energy X-ray absorptiometry (C = 35/149,
L = 6/19 articles) and bio impedance analysis (C = 23/149, L = 2/19
articles) were the most frequently utilised techniques. A third of
included articles (C = 53/149, L = 5/19) measured both muscle strength
and muscle mass within the studied populations.
3.2. Cross-sectional analysis of inflammation and muscle strength
CRP, IL-6 and TNFα were the most frequently used markers to assess
the relationship between inflammation with muscle strength (Supple­
mentary Fig. 1). Fig. 2 describes the meta-analysis for the association
between CRP and muscle strength sub grouped by population and sex
and stratified by muscle strength measurement. CRP was inversely
associated with handgrip strength (r = − 0.10, p < 0.001) and knee
extension strength (r = − 0.18, p < 0.001), which was independent of
sex. Higher IL-6 was associated with lower handgrip strength (r =
− 0.13, p < 0.001) and knee extension strength (r = − 0.11, p < 0.001).
IL-6 had a slightly stronger association with handgrip strength in some
populations compared to others (menopause: r = − 0.18, p < 0.01,
kidney disease: r = − 0.17, p < 0.001) and this relationship was strongest
in cardiovascular disease (CVD) populations for IL-6 with knee extension
3
Ageing Research Reviews 64 (2020) 101185
strength (r = − 0.39, p < 0.001). When sub grouped by sex, higher IL-6
and lower handgrip strength (r = − 0.15, p < 0.001) and knee extension
strength (r = − 0.31, p < 0.001) were observed in males (Fig. 3). TNFα
was inversely associated with handgrip strength (r = − 0.08, p < 0.001)
and knee extension strength (r = − 0.13, p = 0.01), which was dependent
on the population. Cancer cohorts had the highest correlation of TNFα
with handgrip strength (r = − 0.34, p < 0.001), and CVD cohorts had the
highest correlation with TNFα and knee extension strength (r = − 0.39, p
< 0.001). When stratifying by sex, higher TNFα and low knee extension
strength was strongest in males (r = − 0.32, p < 0.001) (Fig. 4). Higher
levels of Growth Differentiation Factor (GDF)15 and IL-8 were signifi­
cantly associated with lower handgrip strength (r = − 0.32, p < 0.001
and r = − 0.33, p < 0.001 respectively) and higher levels of GDF15 was
associated with lower knee extension strength (r = − 0.31, p < 0.001)
(Supplementary Fig. 2).
3.3. Cross-sectional analysis of inflammation and muscle mass
CRP, IL-6 and TNFα were the most frequently used markers to assess
inflammation with muscle mass (Supplementary Fig. 3); the overall
meta-analysis is given in Fig. 5 and the detailed meta-analysis is given in
Supplementary Fig. 4. Overall higher levels of CRP (r = − 0.12, p <
0.001), IL-6 (r = − 0.09, p < 0.001), and TNFα (r = − 0.15, p < 0.001)
were significantly associated with lower muscle mass. The relationship
between inflammatory markers and muscle mass was dependent on the
population for CRP (community dwelling r = − 0.20, p < 0.001; CVD r =
− 0.17, p < 0.001, kidney disease r = − 0.10, p < 0.06), IL-6 (community
dwelling r = − 0.08, p < 0.001, CVD r = − 0.25, p < 0.001, kidney disease
r = − 0.15, p = 0.02) and TNFα (community dwelling r = − 0.04, p =
C.S.L. Tuttle et al. Ageing Research Reviews 64 (2020) 101185

Table 2 4. Discussion
Summary of inflammatory markers used to assess systemic inflammation.
Inflammatory Cross Sectional articles (N = Longitudinal articles (N = Higher levels of circulating inflammatory cytokines are associated
Markers 149) 19) with lower skeletal muscle strength and muscle mass. While previous
CRP, n (%) 89 (60) 12 (63) systematic reviews have demonstrated a relationship between inflam­
GDF-11, n (%) 1 (0.6) mation and sarcopenia, this is the first review to directly analyse the
GDF-15, n (%) 4 (2.7) relationship between systemic inflammation and muscle strength and
GM-CSF, n (%) 3 2.0 – muscle mass independently. The association between inflammation and
IFNγ, n (%) 5 (3.3)
muscle strength and mass is most often investigated using CRP, IL-6 and
–
IFNα, n (%) 2 (1.3) –
IL-1, n (%) 3 (2.0) 1 (5.3) TNFα. However, this review has identified that the strength of this linear
IL-1β, n (%) 10 (6.7) 1 (5.3) association maybe variable and dependent upon populations and sex.
IL-1ra, n (%) 6(4.0) 1 (5.3) CRP, a marker of both acute and chronic phase inflammation, is often
IL-2, n (%) 5 (3.4) –
used in clinical practice to evaluate the inflammatory state of an indi­
IL-2 r, n (%) 5 (3.4) 2 (10.5)
IL-4, n (%) 7 (4.7) – vidual. CRP is known to be heightened in response to infection and
IL-5, n (%) 5 (3.4) – injury. Furthermore, high levels of CRP are associated with a higher risk
IL-6, n (%) 89 (60) 15 (78.9) of the development of chronic diseases such as, type 2 diabetes, car­
IL-6 r, n (%) 5(3.4 2 (10.5) diovascular disease and sarcopenia, a combination of low muscle mass,
IL-7, n (%) 2 (1.3)
strength and physical performance (Bano et al., 2017; Cesari et al., 2003;
–
IL-8, n (%) 13 (8.7 –
IL-10, n (%) 12 (8.1 – Freeman et al., 2002; Koenig et al., 2008). The wide and easily accessible
IL-12, n (%) 6 (4.0) – availability of CRP may explain why it has been utilised most often by
IL-13, n (%) 5 (3.4) – this research field to assess the relationship between systemic inflam­
IL-15, n (%) 4 (2.7) –
mation and lower muscle strength or muscle mass. Interestingly, despite
IL-15rα, n (%) 1 (0.6)
IL-17, n (%) 3 (3) – observing a significant inverse association between CRP levels and
IP-10, n (%) 2 (1.3) muscle strength and muscle mass, it is not known if CRP directly acts
MCP-1, n (%) 3 (2.0) – upon muscle to cause muscle atrophy.
MIG, n (%) 2 (1.3) – This analysis highlights a stronger association between CRP and
MIP-1α, n (%) 2 (1.3)
muscle mass than IL-6 and muscle mass in community dwelling pop­
–
MIP-1β, n (%) 2 (1.3) –
sTNFrI, n (%) 3 (2.0) 1 (5.3) ulations. Elevated CRP levels have also been associated with sarcopenia,
sTNFrII, n (%) 4(2.7) 2 (10.5) but not with IL-6 and TNFα (Bano et al., 2017). It is possible that the
TNFα, n (%) 58(38.9) 8 (42.1) observed association reflects a higher level of inflammation within the
Abbreviations: CRP – C reactive protein, GDF – Growth/differentiation factor, body however, when other chronic diseases are involved other inflam­
GM-CSF – Granulocyte Macrophage Colony Stimulating Factor, IFN – Interferon, matory cytokines such as IL-6, may directly act upon muscle (Londhe
IL- Interleukin, MCP – monocyte chemoattractant protein, MIG – Monokine and Guttridge 2015).
induced by gamma interferon, MIP – Macrophage inflammatory protein, TNF- IL-6 has long been recognised as a key cytokine that promotes muscle
Tumor Necrosis Factor. anabolism or catabolism depending upon the in vivo environment
(Belizário et al., 2016). As part of the inflammatory secretome, IL-6 is
0.28, CVD r = − 0.40, p < 0.001, kidney disease r = − 0.19, p = 0.08). secreted by immune cells in response to tissue infection and/or tissue
The relationship of IL-6, TNFα and muscle mass was dependent on sex damage. Furthermore, chronic low-grade inflammation is associated
(IL-6: female r = 0.04, p = 0.60; male r = − 0.11, p < 0.001; TNFα: female with prolonged exposure to IL-6 signalling. IL-6 is also a known myo­
r = − 0.08, p < 0.001; male r = − 0.21, p < 0.001). kine, produced by skeletal muscle and secreted from active skeletal
muscle during exercise and is likely to improve glucose tolerance and
insulin sensitivity post exercise. As such a temporal higher level of IL-6
3.4. Longitudinal analysis between inflammation and muscle strength and
can be beneficial (Pedersen and Febbraio, 2006). However, prolonged
mass
exposure to IL-6 has been shown to facilitate muscle atrophy by blunting
muscle anabolism and energy homeostasis and may also directly
Altogether, 19 longitudinal studies investigating the association be­
mediate muscle catabolism (Belizário et al., 2016).
tween inflammatory markers and muscle strength and/or muscle mass
In this analysis we observed a stronger association of IL-6 and lower
were included in this review (Supplementary Table 2b) (Aleman et al.,
muscle mass in populations with age-related diseases such as cardio­
2011; Bartali et al., 2012; Bickerstaffe et al., 2015; Ferrucci et al., 2002;
vascular disease. Furthermore, this relationship was strongest in men. A
Haider et al., 2017; Hyun-Hun et al., 2019; Ihalainen et al., 2019; Li
meta-analysis investigating sex effects on the relationship between IL-6
et al., 2019; McMahon et al., 2019; Miura et al., 2015; Newman et al.,
and handgrip strength also found a stronger negative correlation be­
2016; Rolland and Perry (2007); Sanchez-Ramirez et al., 2014; Sanders
tween plasma IL-6 and handgrip strength in men compared to women
et al., 2014; Schaap et al., 2009, 2006; Sergi et al., 2011; Stenholm et al.,
(Mikó et al., 2018). The impact sex has on the relationship between
2010; Taaffe et al., 2000). CRP, IL-6 and TNFα were the most utilised
inflammation and muscle is important to consider (Anderson et al.,
inflammatory markers. Overall there was an association between higher
2017; Gubbels Bupp, 2015) and may differ depending on the cytokine.
inflammatory cytokines and decreasing muscle strength and/or mass
Furthermore, it has previously been shown that the sole action of IL-6 is
over time (Supplementary Table 3), however, this association did not
not enough to induce muscle wasting rather, the catabolic effect of IL-6
appear to be related to follow-up time (Schaap et al., 2009, 2006).
is dependent on the synergistic interaction with other factors mediating
the inflammatory response (Belizário et al., 2016). This may explain
3.5. Publication bias why a significant but overall weak relationship between IL-6 and muscle
strength was observed within community dwelling cohorts. The higher
Publication bias was assessed for all outcomes via visually inspecting IL-6 level associated with ageing may not be enough to induce the
the asymmetry of the funnel plot (Supplementary Fig. 5). The funnel plot catabolic effect required for muscle wasting. However, the concomitant
including all data points demonstrated asymmetry. This, combined with activity of other cytokines such as TNFα may create the physiological
Egger’s regression intercept analysis, indicated publication bias towards environment required that ultimately leads to muscle atrophy.
positive findings (p = 0.001). TNFα released from diseased tissues has been shown to exert

4
C.S.L. Tuttle et al. Ageing Research Reviews 64 (2020) 101185

Fig. 2. Association between CRP and muscle strength; subgrouped by population and sex for A. handgrip strength (HGS), B. knee extension strength (KE), C. other
muscle strength measures.
Figure legend: #Assoc – Number of Associations; I2 – Heterogeneity; other muscle strength measures – knee flexion, hip extension, ankle extension, neck extension,
neck flexion, 1RM, 10RM, strength score. Immune population includes Cytomegalovirus, Human immunodeficiency virus and Lupus, Metabolic population includes
obesity and type 2 diabetes, Bone disease includes osteoarthritis and rheumatoid arthritis.

5
C.S.L. Tuttle et al. Ageing Research Reviews 64 (2020) 101185

Fig. 3. The association between IL-6 and muscle strength; subgrouped by population and sex for A. handgrip strength (HGS), B. knee extension strength (KE), C.
other muscle strength measures.
Figure legend: #Assoc – Number of Associations; I2 – Heterogeneity; HGS - Handgrip strength; other muscle strength measures – knee flexion, hip extension, ankle
extension, neck extension, neck flexion, 1RM, 10RM, strength score. Immune population includes Cytomegalovirus, Human immunodeficiency virus and Lupus,
Metabolic population includes obesity and type 2 diabetes, Bone disease includes osteoarthritis and rheumatoid arthritis.

6
C.S.L. Tuttle et al. Ageing Research Reviews 64 (2020) 101185

Fig. 4. The association between TNFα and muscle strength; subgrouped by population and sex for A. handgrip strength (HGS), B. knee extension strength (KE), C.
other muscle strength measures.
Figure legend: #Assoc – Number of Associations; I2 – Heterogeneity; HGS - Handgrip strength; other muscle strength measures – knee flexion, hip extension, ankle
extension, neck extension, neck flexion, 1RM, 10RM, strength score. Immune population includes Cytomegalovirus, Human immunodeficiency virus and Lupus,
Metabolic population includes obesity and type 2 diabetes, Bone disease includes osteoarthritis and rheumatoid arthritis.

7
C.S.L. Tuttle et al. Ageing Research Reviews 64 (2020) 101185

Fig. 5. The association between (A.) CRP, (B.) IL-6, (C.)

TNFα and muscle mass (MM); subgrouped by population
and sex.
Figure legend: #Assoc – Number of Associations, I2 –
Heterogeneity, Gastrointestinal populations (GIT) include
Crohn’s Disease, inflammatory bowel disease and liver
disease, Immune population includes Cytomegalovirus,
Human immunodeficiency virus and Lupus, Metabolic
population includes obesity and type 2 diabetes, Bone
disease includes osteoarthritis and rheumatoid arthritis.

8
C.S.L. Tuttle et al.
endocrine effects on skeletal muscle (Powers et al., 2016). TNFα is a
pro-inflammatory cytokine that directly acts upon skeletal muscle to
depress specific force. This decline in specific force has been shown
through various in vitro and in vivo experiments using exogenous TNF
(Alloatti et al., 2000), systemic administration of TNF in dogs (Wilcox
et al., 1994) and overexpression of TNF in mice (Wolkorte et al., 2015).
As such, it is not surprising that higher systemic TNFα levels are asso­
ciated with lower muscle strength and muscle mass.
TNF signalling is triggered by ligand/receptor interactions at the
cells surface. Skeletal muscle fibres constitutively express two TNF re­
ceptors, TNFR1 and TNFR2 (Powers et al., 2016). Interestingly, in vitro
studies have demonstrated that muscle responses to TNF are triggered
by activation of TNFR1 rather than TNFR2 (Hardin et al., 2008). How­
ever, in this analysis a stronger association was observed between sys­
temic levels of TNFR2 and lower muscle strength/mass compared to
TNFR1. Furthermore, a sex difference may exist with a stronger negative
correlation between TNFα and muscle strength and mass observed in
men. Therefore, the interplay between TNFα and IL-6 and its impact on
muscle maybe sex specific. However, the male populations included in
this analysis also often had chronic diseases. Further analysis is required
to untangle the relationship interplay between chronic disease, sex, and
muscle.
In addition to CRP, IL-6 and TNFα, other inflammatory markers
investigated in this review showed an inverse relationship with muscle
strength and muscle mass such as GDF15. GDF15 is a cytokine that has
been associated with ageing (Fujita et al., 2016). However, whether
GDF15 is beneficial or detrimental to skeletal muscle is contentious. In
this analysis higher levels of GDF15 was associated with lower muscle
strength and mass. GDF15 is able to induce muscle fibre apoptosis via
phosphorylation of STAT3 (Tang et al., 2019) and this may explain why
higher levels of GDF15 are associated with lower muscle strength and
mass, however it is important to note that the analysis performed here
does not demonstrate causality.
There appears to be sufficient evidence to conclude that higher sys­
temic inflammation is associated with lower muscle strength and muscle
mass in humans. Furthermore, longitudinal studies also confirm this
relationship exists over time, but it is important to note that some of
these associations while significant were weak. The cross-sectional as­
sociation of single inflammatory markers with muscle strengths and
mass and the less consistent longitudinal associations, questions the
temporal relationship between inflammatory markers and muscle
measures. Muscle strength and mass might decline prior to an increase in
systemic inflammation. Furthermore, skeletal muscle can actively alter
the pro- and anti-inflammatory immune system, regulating innate and
adaptive immune responses. Chronic low-grade systemic inflammation
may occur as a direct result of low muscle mass (Looijaard et al., 2020).
However, the stronger relationship between higher inflammation and
lower muscle mass reported here within specific populations such as,
cardiovascular disease, would suggest an alternate theory. As such other
pathophysiology associated with low muscle strength and mass might
also contribute to high systemic inflammation.
This review is not without limitations. The overall meta-analysis for
each cytokine demonstrated weak correlation coefficient that were
statistically significant. Often when an effect size is small but statistically
significant it is due to a large sample size. Given the combined popula­
tion of the cross-sectional studies is 76,899 the impact of sample size on
this analysis cannot be discounted. However, it is important to note that
not all studies included in the systematic review could be included in the
meta-analysis. Furthermore, this analysis highlights that a linear
approach to examine the association between systemic inflammation
and muscle may not reflect the true relationship between the two pa­
rameters, indeed some publications have described a quadratic rela­
tionship between systemic inflammation and muscle strength decline
(Tay et al., 2019; Rosenberg et al., 2019). It was not possible to stratify
the overall analysis by age. Higher chronological age is known to impact
both chronic inflammation and muscle strength and mass (Beenakker
9
Ageing Research Reviews 64 (2020) 101185
et al., 2010). The association between inflammation and lower muscle
strength or mass reported here could be stronger in older populations.
The search strategy was designed to be broad and inclusive; all reported
markers of inflammation were included; this has led to some articles
contributing multiple associations within the meta-analysis. Further­
more, some articles report using the same cohort e.g. InCHIANTI (Bartali
et al., 2012; Stenholm et al., 2010) but used different techniques to
measure muscle strength such as handgrip strength (Stenholm et al.,
2010) and knee extension (Bartali et al., 2012). This is likely to have a
positive bias on the power and significance of the overall meta-analysis.
Finally, when interpreting the findings reported here, publication and
reporting bias must also be considered.
The findings of this review conclusively demonstrate a significant
association between higher levels of circulating inflammatory markers
and lower skeletal muscle strength and muscle mass and the strength of
this relationship differs depending upon population and sex.
Funding
N/A.
CRediT authorship contribution statement
Camilla S.L. Tuttle: Data curation, Investigation, Writing - original
draft, Writing - review & editing. Lachlan A.N. Thang: Data curation,
Investigation, Writing - original draft. Andrea B. Maier: Data curation,
Conceptualization, Writing - review & editing.
Declaration of Competing Interest
None declared.
Acknowledgements
The authors thank Mr. Jimmy Ky (JK) for his assistance with
screening articles and Mr. Patrick Condron, senior librarian University
of Melbourne, for his assistance with developing the search strategy for
this review.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.arr.2020.101185.
References
Aleman, H., Esparza, J., Ramirez, F.A., Astiazaran, H., Payette, H., 2011. Longitudinal
evidence on the association between interleukin-6 and C-reactive protein with the
loss of total appendicular skeletal muscle in free-living older men and women. Age
Ageing 40, 469–475.
Ali, S., Garcia, J.M., 2014. Sarcopenia, cachexia and aging: diagnosis, mechanisms and
therapeutic options – a mini-review. Gerontology 60, 294–305.
Alloatti, G., Penna, C., Mariano, F., Camussi, G., 2000. Role of NO and PAF in the
impairment of skeletal muscle contractility induced by TNF-alpha. Am. J. Physiol.
Regul. Integr. Comp. Physiol. 279, R2156–R2163.
Anderson, L.J., Liu, H., Garcia, J.M., 2017. Sex differences in muscle wasting. Adv. Exp.
Med. Biol. 1043, 153–197.
Bano, G., Trevisan, C., Carraro, S., Solmi, M., Luchini, C., Stubbs, B., Manzato, E.,
Sergi, G., Veronese, N., 2017. Inflammation and sarcopenia: a systematic review and
meta-analysis. Maturitas 96, 10–15.
Bartali, B., Frongillo, E.A., Stipanuk, M.H., Bandinelli, S., Salvini, S., Palli, D., Morais, J.
A., Volpato, S., Guralnik, J.M., Ferrucci, L., 2012. Protein intake and muscle strength
in older persons: does inflammation matter? J. Am. Geriatr. Soc.
Beenakker, K.G., Ling, C.H., Meskers, C.G., de Craen, A.J., Stijnen, T., Westendorp, R.G.,
Maier, A.B., 2010. Patterns of muscle strength loss with age in the general
population and patients with a chronic inflammatory state. Ageing Res. Rev. 9,
431–436.
Belizário, J.E., Fontes-Oliveira, C.C., Borges, J.P., Kashiabara, J.A., Vannier, E., 2016.
Skeletal muscle wasting and renewal: a pivotal role of myokine IL-6. Springerplus 5,
619.
C.S.L. Tuttle et al.
Bickerstaffe, A., Beelen, A., Lutter, R., Nollet, F., 2015. Elevated plasma inflammatory
mediators in post-polio syndrome: No association with long-term functional decline.
J. Neuroimmunol. 289, 162–167.
Can, B., Kara, O., Kizilarslanoglu, M.C., Arik, G., Aycicek, G.S., Sumer, F., Civelek, R.,
Demirtas, C., Ulger, Z., 2017. Serum markers of inflammation and oxidative stress in
sarcopenia. Aging Clin. Exp. Res. 29, 745–752.
Cesari, M., Penninx, B.W.J.H., Newman, A.B., Kritchevsky, S.B., Nicklas, B.J., Sutton-
Tyrrell, K., Tracy, R.P., Rubin, S.M., Harris, T.B., Pahor, M., 2003. Inflammatory
markers and cardiovascular disease (the health, aging and body composition [health
ABC] study). Am. J. Cardiol. 92, 522–528.
Chhetri, J.K., de Souto Barreto, P., Fougere, B., Rolland, Y., Vellas, B., Cesari, M., 2018.
Chronic inflammation and sarcopenia: a regenerative cell therapy perspective. Exp.
Gerontol. 103, 115–123.
Chung, H.Y., Kim, D.H., Lee, E.K., Chung, K.W., Chung, S., Lee, B., Seo, A.Y., Chung, J.H.,
Jung, Y.S., Im, E., Lee, J., Kim, N.D., Choi, Y.J., Im, D.S., Yu, B.P., 2019. Redefining
chronic inflammation in aging and age-related diseases: proposal of the
senoinflammation concept. Aging Dis. 10, 367–382.
Cruz-Jentoft, A.J., Bahat, G., Bauer, J., Boirie, Y., Bruyere, O., Cederholm, T., Cooper, C.,
Landi, F., Rolland, Y., Sayer, A.A., Schneider, S.M., Sieber, C.C., Topinkova, E.,
Vandewoude, M., Visser, M., Zamboni, M., 2019. Sarcopenia: revised European
consensus on definition and diagnosis. Age Ageing 48, 16–31.
Ferrucci, L., Penninx, B.W.J.H., Volpato, S., Harris, T.B., Bandeen-Roche, K., Balfour, J.,
Leveille, S.G., Fried, L.P., Guralnik, J.M., 2002. Change in muscle strength explains
accelerated decline of physical function in older women with high interleukin-6
serum levels. J. Am. Geriatr. Soc. 50, 1947–1954.
Ferrucci, L., Corsi, A., Lauretani, F., Bandinelli, S., Bartali, B., Taub, D.D., Guralnik, J.M.,
Longo, D.L., 2005. The origins of age-related proinflammatory state. Blood 105,
2294–2299.
Fielding, R.A., Vellas, B., Evans, W.J., Bhasin, S., Morley, J.E., Newman, A.B., Abellan
van Kan, G., Andrieu, S., Bauer, J., Breuille, D., Cederholm, T., Chandler, J., De
Meynard, C., Donini, L., Harris, T., Kannt, A., Keime Guibert, F., Onder, G.,
Papanicolaou, D., Rolland, Y., Rooks, D., Sieber, C., Souhami, E., Verlaan, S.,
Zamboni, M., 2011. Sarcopenia: an undiagnosed condition in older adults. Current
consensus definition: prevalence, etiology, and consequences. International working
group on sarcopenia. J. Am. Med. Dir. Assoc. 12, 249–256.
Franceschi, C., Bonafe, M., Valensin, S., Olivieri, F., De Luca, M., Ottaviani, E., De
Benedictis, G., 2000. Inflamm-aging. An evolutionary perspective on
immunosenescence. Ann. N. Y. Acad. Sci. 908, 244–254.
Freeman, D.J., Norrie, J., Caslake, M.J., Gaw, A., Ford, I., Lowe, G.D.O., O’Reilly, D.S.J.,
Packard, C.J., Sattar, N., West of Scotland Coronary Prevention, S, 2002. C-reactive
protein is an independent predictor of risk for the development of diabetes in the
West of Scotland Coronary Prevention Study. Diabetes 51, 1596–1600.
Fujita, Y., Taniguchi, Y., Shinkai, S., Tanaka, M., Ito, M., 2016. Secreted growth
differentiation factor 15 as a potential biomarker for mitochondrial dysfunctions in
aging and age-related disorders. Geriatr. Gerontol. Int. 16 (Suppl 1), 17–29.
Gubbels Bupp, M.R., 2015. Sex, the aging immune system, and chronic disease. Cell.
Immunol. 294, 102–110.
Haddad, F., Zaldivar, F., Cooper, D.M., Adams, G.R., 2005. IL-6-induced skeletal muscle
atrophy. J. Appl. Physiol. 98, 911–917.
Haider, S., Grabovac, I., Winzer, E., Kapan, A., Schindler, K.E., Lackinger, C., Titze, S.,
Dorner, T.E., 2017. Change in inflammatory parameters in prefrail and frail persons
obtaining physical training and nutritional support provided by lay volunteers: a
randomized controlled trial. PLoS One 12.
Hardin, B.J., Campbell, K.S., Smith, J.D., Arbogast, S., Smith, J., Moylan, J.S., Reid, M.B.,
2008. TNF-alpha acts via TNFR1 and muscle-derived oxidants to depress myofibrillar
force in murine skeletal muscle. J. Appl. Physiol. 104, 694–699.
Hyun-Hun, J., Min-Ki, J., Do-Kyum, M., Yun-Hwan, K., Eun-Hee, K., Garam, H., Jae-
Hyun, P., Seon-Hong, B., Il-Kyu, P., Cao-You, S., Gwon-Min, K., Dong-Hyun, K.,
Sang-Kab, P., 2019. Effects of combined exercise on appendicular muscle mass, self-
reliance fitness and arteriosclerosis adhesion molecules in elderly women. Arch.
Budo 15, 103–112.
Ihalainen, J.K., Hackney, A.C., Taipale, R.S., 2019. Changes in inflammation markers
after a 10-week high-intensity combined strength and endurance training block in
women: the effect of hormonal contraceptive use. J. Sci. Med. Sport 22, 1044–1048.
Koenig, W., Khuseyinova, N., Baumert, J., Meisinger, C., 2008. Prospective study of high-
sensitivity C-reactive protein as a determinant of mortality: results from the
MONICA/KORA Augsburg Cohort Study, 1984–1998. Clin. Chem. 54, 335–342.
Kwak, J.Y., Hwang, H., Kim, S.K., Choi, J.Y., Lee, S.M., Bang, H., Kwon, E.S., Lee, K.P.,
Chung, S.G., Kwon, K.S., 2018. Prediction of sarcopenia using a combination of
multiple serum biomarkers. Sci. Rep. 8, 8574.
Li, X., Moody, M.R., Engel, D., Walker, S., Clubb Jr, F.J., Sivasubramanian, N., Mann, D.
L., Reid, M.B., 2000. Cardiac-specific overexpression of tumor necrosis factor-alpha
causes oxidative stress and contractile dysfunction in mouse diaphragm. Circulation
102, 1690–1696.
Li, C.W., Yu, K., Shyh-Chang, N., Li, G.X., Jiang, L.J., Yu, S.L., Xu, L.Y., Liu, R.J., Guo, Z.
J., Xie, H.Y., Li, R.R., Ying, J., Li, K., Li, D.J., 2019. Circulating factors associated
with sarcopenia during ageing and after intensive lifestyle intervention. J. Cachexia
Sarcopenia Muscle 10, 586–600.
Liberati, A., Altman, D.G., Tetzlaff, J., Mulrow, C., Gøtzsche, P.C., Ioannidis, J.P.A.,
Clarke, M., Devereaux, P.J., Kleijnen, J., Moher, D., 2009. The PRISMA statement for
reporting systematic reviews and meta-analyses of studies that evaluate health care
interventions: explanation and elaboration. PLoS Med. 6, e1000100.
Londhe, P., Guttridge, D.C., 2015. Inflammation induced loss of skeletal muscle. Bone 80,
131–142.
10
Ageing Research Reviews 64 (2020) 101185
Looijaard, S.M.L.M., te Lintel Hekkert, M.L., Wüst, R.C.I., Otten, R.H.J., Meskers, C.G.M.,
Maier, A.B., 2020. Pathophysiological mechanisms explaining poor clinical outcome
of older cancer patients with low skeletal muscle mass. Acta Physiol. e13516.
McMahon, G., Morse, C.I., Winwood, K., Burden, A., Onambele, G.L., 2019. Circulating
tumor necrosis factor alpha may modulate the short-term detraining induced muscle
mass loss following prolonged resistance training. Front. Physiol. 10, 527.
Mikó, A., Pótó, L., Mátrai, P., Hegyi, P., Füredi, N., Garami, A., Illés, A., Solymár, M.,
Vincze, Á., Balaskó, M., Pár, G., Sarlós, P., Bajor, J., Tenk, J., Rostás, I., Pétervári, E.,
2018. Gender difference in the effects of interleukin-6 on grip strength – a systematic
review and meta-analysis. BMC Geriatr. 18, 107.
Miura, T., Mitsunaga, S., Ikeda, M., Shimizu, S., Ohno, I., Takahashi, H., Furuse, J.,
Inagaki, M., Higashi, S., Kato, H., Terao, K., Ochiai, A., 2015. Characterization of
patients with advanced pancreatic cancer and high serum interleukin-6 levels.
Pancreas 44, 756–763.
Newman, A.B., Sanders, J.L., Kizer, J.R., Boudreau, R.M., Odden, M.C., Zeki Al
Hazzouri, A., Arnold, A.M., 2016. Trajectories of function and biomarkers with age:
the CHS All Stars Study. Int. J. Epidemiol. 45, 1135–1145.
Pacifico, J., Geerlings, M.A.J., Reijnierse, E.M., Phassouliotis, C., Lim, W.K., Maier, A.B.,
2020. Prevalence of sarcopenia as a comorbid disease: a systematic review and meta-
analysis. Exp. Gerontol. 131, 110801.
Pedersen, B.K., Febbraio, M., 2006. Exercise and interleukin-6 action. Expert Rev.
Endocrinol. Metab. 1, 319–321.
Pedersen, M., Bruunsgaard, H., Weis, N., Hendel, H.W., Andreassen, B.U., Eldrup, E.,
Dela, F., Pedersen, B.K., 2003. Circulating levels of TNF-alpha and IL-6-relation to
truncal fat mass and muscle mass in healthy elderly individuals and in patients with
type-2 diabetes. Mech. Ageing Dev. 124, 495–502.
Powers, S.K., Lynch, G.S., Murphy, K.T., Reid, M.B., Zijdewind, I., 2016. Disease-induced
skeletal muscle atrophy and fatigue. Med. Sci. Sports Exerc. 48, 2307–2319.
Reijnierse, E.M., de van der Schueren, M.A.E., Trappenburg, M.C., Doves, M., Meskers, C.
G.M., Maier, A.B., 2017. Lack of knowledge and availability of diagnostic equipment
could hinder the diagnosis of sarcopenia and its management. PLoS One 12,
e0185837.
Rolland, Y.M., Perry, H.M., Patrick, P., Banks, W.A., Morley, J.E., 2007. Loss of
appendicular muscle mass and loss of muscle strength in young postmenopausal
women. J. Gerontol. A Biol. Sci. Med. Sci. 62, 330–335.
Rosenberg, B.J., Hirano, M., Quinzii, C.M., Colantuoni, E., Needham, D.M., Lederer, D.J.,
Baldwin, M.R., 2019. Growth differentiation factor-15 as a biomarker of strength
and recovery in survivors of acute respiratory failure. Thorax 74, 1099–1101.
Sanchez-Ramirez, D.C., van der Leeden, M., van der Esch, M., Roorda, L.D.,
Verschueren, S., van Dieen, J.H., Dekker, J., Lems, W.F., 2014. Elevated C-reactive
protein is associated with lower increase in knee muscle strength in patients with
knee osteoarthritis: a 2-year follow-up study in the Amsterdam Osteoarthritis (AMS-
OA) cohort. Arthritis Res. Ther. 16 (3) (no pagination).
Sanders, J.L., Ding, V., Arnold, A.M., Kaplan, R.C., Cappola, A.R., Kizer, J.R.,
Boudreau, R.M., Cushman, M., Newman, A.B., 2014. Do changes in circulating
biomarkers track with each other and with functional changes in older adults?
J. Gerontol. Ser. A, Biol. Sci. Med. Sci. 69, 174–181.
Schaap, L.A., Pluijm, S.M.F., Deeg, D.J.H., Visser, M., 2006. Inflammatory markers and
loss of muscle mass (Sarcopenia) and strength. Am. J. Med. 119, 526.e529-526.e517.
Schaap, L.A., Pluijm, S.M., Deeg, D.J., Harris, T.B., Kritchevsky, S.B., Newman, A.B.,
Colbert, L.H., Pahor, M., Rubin, S.M., Tylavsky, F.A., Visser, M., 2009. Higher
inflammatory marker levels in older persons: associations with 5-year change in
muscle mass and muscle strength. J. Gerontol. Ser. A Biol. Sci. Med. Sci. 64,
1183–1189.
Sergi, G., Sarti, S., Mosele, M., Ruggiero, E., Imoscopi, A., Miotto, F., Bolzetta, F.,
Inelmen, E.M., Manzato, E., Coin, A., 2011. Changes in healthy elderly women’s
physical performance: a 3-year follow-up. Exp. Gerontol. 46, 929–933.
Souza, V.Ad., Oliveira, D., Barbosa, S.R., Corrêa, J.Od.A., Colugnati, F.A.B., Mansur, H.
N., Fernandes, N.Md.S., Bastos, M.G., 2017. Sarcopenia in patients with chronic
kidney disease not yet on dialysis: analysis of the prevalence and associated factors.
PLoS One 12, e0176230.
Stenholm, S., Maggio, M., Lauretani, F., Bandinelli, S., Ceda, G.P., Di Iorio, A.,
Giallauria, F., Guralnik, J.M., Ferrucci, L., 2010. Anabolic and catabolic biomarkers
as predictors of muscle strength decline: the InCHIANTI study. Rejuvenation Res. 13,
3–11.
Taaffe, D.R., Harris, T.B., Ferrucci, L., Rowe, J., Seeman, T.E., 2000. Cross-sectional and
prospective relationships of interleukin-6 and c-reactive protein with physical
performance in elderly persons: MacArthur studies of successful aging. J. Gerontol.
Ser. A Biol. Sci. Med. Sci. 55, M709–M715.
Tang, H., Inoki, K., Brooks, S.V., Okazawa, H., Lee, M., Wang, J., Kim, M., Kennedy, C.L.,
Macpherson, P.C.D., Ji, X., Van Roekel, S., Fraga, D.A., Wang, K., Zhu, J., Wang, Y.,
Sharp, Z.D., Miller, R.A., Rando, T.A., Goldman, D., Guan, K.L., Shrager, J.B., 2019.
mTORC1 underlies age-related muscle fiber damage and loss by inducing oxidative
stress and catabolism. Aging Cell 18, e12943.
Tay, J., Goss, A.M., Locher, J.L., Ard, J.D., Gower, B.A., 2019. Physical function and
strength in relation to inflammation in older adults with obesity and increased
cardiometabolic risk. J. Nutr. Health Aging 23, 949–957.
Wilcox, P.G., Wakai, Y., Walley, K.R., Cooper, D.J., Road, J., 1994. Tumor necrosis factor
alpha decreases in vivo diaphragm contractility in dogs. Am. J. Respir. Crit. Care
Med. 150, 1368–1373.
Wolkorte, R., Heersema, D.J., Zijdewind, I., 2015. Muscle fatigability during a sustained
index finger abduction and depression scores are associated with perceived fatigue in
C.S.L. Tuttle et al.
patients with relapsing-remitting multiple sclerosis. Neurorehabil. Neural Repair 29,
796–802.
Yeung, S.S.Y., Reijnierse, E.M., Pham, V.K., Trappenburg, M.C., Lim, W.K., Meskers, C.G.
M., Maier, A.B., 2019a. Sarcopenia and its association with falls and fractures in
older adults: a systematic review and meta-analysis. J. Cachexia Sarcopenia Muscle
10, 485–500.
11
Ageing Research Reviews 64 (2020) 101185
Yeung, S.S.Y., Reijnierse, E.M., Trappenburg, M.C., Meskers, C.G.M., Maier, A.B., 2019b.
Current knowledge and practice of Australian and New Zealand health-care
professionals in sarcopenia diagnosis and treatment: time to move forward!
Australas. J. Ageing.