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Review
The role of microRNAs in regulating inflammation and
exercise-induced adaptations in rheumatoid arthritis
Christopher Balchin
1
, Ai Lyn Tan
2,3
, Oliver J. Wilson
1
, Jim McKenna
1
,
Antonios Stavropoulos-Kalinoglou
1,
*
1
Carnegie School of Sport, Leeds Beckett University, Leeds, UK
2
Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Chapel Allerton Hospital, Leeds, UK
3
NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK
*Correspondence to: Antonios Stavropoulos-Kalinoglou, Carnegie School of Sport, Leeds Beckett University, Headingley Campus, 225 Fairfax Hall,
Churchwood Avenue, Leeds LS6 3QS, UK. E-mail: a.stavropoulos@leedsbeckett.ac.uk
Abstract
MicroRNAs (miRNAs) are endogenously generated single-stranded RNAs that play crucial roles in numerous biological processes, such as cell
development, proliferation, differentiation, metabolism and apoptosis. They negatively regulate target gene expression by repressing translation
of messenger RNA into a functional protein. Several miRNAs have been implicated in the development and progression of RA. They are involved
in inflammatory and immune processes and are associated with susceptibility to RA and disease activity. They are also considered to be potential
markers of disease activity or even therapeutic targets. Likewise, several miRNAs are affected acutely by exercise and regulate exercise-related
adaptations in the skeletal muscle and cardiovascular system and aerobic fitness. Interestingly, some miRNAs affected by exercise are also
important in the context of RA. Investigating these might increase our understanding of the effects of exercise in RA and improve exercise
prescription and, potentially, disease management. In this review, we focus on the miRNAs that are associated with both RA and exercise and
discuss their roles in (and potential interactions between) RA and exercise-induced adaptations.
Lay Summary
What does this mean for patients?
In this review, we look at the role of microRNAs in rheumatoid arthritis (RA) and how exercise might affect them. MicroRNAs are very small
molecules that travel around the body and help in a lot of biological functions, such as how cells work, when they multiply and when they die. In
RA, many of these microRNAs are dysregulated (i.e. their levels might be different from those in people without RA). This might be associated
with some of the symptoms of RA, such as joint pain and swelling, inflammation and disease activity. Exercise also affects microRNAs. After we
have exercised, circulating levels of some microRNAs can increase, whereas others decrease. These changes help us to get fitter. What is
currently not known is how microRNAs change when people with RA exercise. We believe that understanding this will help us to develop better
exercise programmes that will improve health and overall quality of life for people with RA.
Keywords: inflammation, microRNAs, aerobic exercise, resistance exercise, physical activity, metabolism, disease activity, arthritis, risk factors, pathogenesis
Introduction
RA is a chronic inflammatory autoimmune condition that pri-
marily affects synovial joints. It is characterized by joint pain,
stiffness and swelling, which can eventually lead to functional
limitations and structural damage to the joints. People with
RA tend to be physically inactive, with low levels of fitness
and a high risk for cardiovascular and metabolic conditions.
Management of RA relies on pharmacological treatments
aiming to reduce inflammation and its associated symptoms.
In recent years, exercise has been included in the management
recommendations for RA [1]. Well-designed exercise pro-
grammes are known to improve fitness, mobility, fatigue,
overall health and quality of life among people with RA [2–
4]. Importantly, exercise is now advocated as a non-
pharmacological treatment for people with difficult-to-treat
RA [5,6] (i.e. people who remain symptomatic despite being
treated based on existing pharmacological protocols [7]).
However, relatively little is known about the biological regu-
lation of these adaptations and how exercise and inflamma-
tion might interact in this respect in RA [8].
Key messages
•MicroRNAs are involved in the pathogenesis and progression of RA and in exercise-induced adaptations.
•Acute exercise changes levels of microRNAs commonly associated with disease progression in RA.
•Understanding the combined effects of exercise and RA on microRNA might help with personalizing exercise prescription and improve
disease management.
Received: 18 July 2022. Accepted: 12 December 2022
V
CThe Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which
permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Rheumatology Advances in Practice,2023, 7, rkac110
https://doi.org/10.1093/rap/rkac110
Review Rheumatolog
y
A
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A relatively new area of investigation, particularly around
the acute effects of exercise on bodily functions, is that of
microRNAs (miRNAs). These are endogenously generated
single-stranded RNAs that are 21–25 nucleotides in length
[9]. More than 2000 miRNAs have been identified in humans
[10], and they play crucial roles in numerous biological pro-
cesses, such as cell development, proliferation, differentiation,
metabolism and apoptosis [11]. They negatively regulate tar-
get gene expression by cleaving messenger RNA (mRNA) and
subsequently repress translation of the mRNA into a func-
tional protein [12]. Furthermore, they are estimated to con-
tribute 1–2% of the whole genome and can regulate 30% of
all protein-encoding genes [9]. Exercise-induced changes in
miRNA levels are thought to regulate chronic adaptations in
skeletal muscle, cardiovascular health and aerobic fitness [13,
14], and they might prove to be useful biomarkers for opti-
mizing exercise prescription for the promotion of health or
improvement of performance.
Moreover, miRNAs are suggested to play regulatory roles
in inflammation and innate immune responses [15–17] and
are essential in T cell activation during adaptive immunity [9].
Abnormalities in miRNA expression can contribute to RA pa-
thology [18–21]. Dysregulation of miRNAs in peripheral
blood mononuclear cells [22,23], T lymphocytes [24], syno-
vial tissue and synovial fibroblasts [18,19] is associated with
joint destruction, amplification of inflammation and degrada-
tion of extracellular matrix [25].
In this narrative review, we discuss some of the key
miRNAs that have been linked to RA and explore the poten-
tial role of exercise in their regulation.
MicroRNAs relevant to RA
A number of different miRNAs have been associated with RA
susceptibility, disease progression and recurrence, in addition
to drug response. Their study might reveal new therapeutic
targets or biomarkers [26].
miR-16 is considered to regulate proliferation and differen-
tiation of Th17 and Treg cells [27]. In normal conditions,
miR-16 targets programmed cell death 4 gene (PDCD4)to
suppress activation of inflammatory macrophages, which
results in suppression of mRNA expression of pro-
inflammatory cytokines TNF-aand IL-6 [28]. Indeed, miR-16
was shown to target the 30untranslated region of TNF-a[22,
29] and thereby, miR-16 might regulate TNF-asignalling
[12], which is crucial for RA pathogenesis. Interestingly, miR-
16 has been found at significantly lower levels in persons with
early RA [30], but upregulated in established RA [30–32].
Nevertheless, miR-16 remains a reliable marker of disease ac-
tivity in people with RA [12,22].
miR-21 levels were also elevated in plasma of people with
RA vs healthy adults [32]. It has been observed that miR-21 is
expressed at higher levels in Treg vs Th17 cells. Also, signal
transducer and activator of transcription 3 (STAT3), a tran-
scription factor necessary for Th17 cell differentiation, is a
target gene for miR-21 [33]. This contributes to an imbalance
of Th17 and Treg cells, which highlights miR-21 as a bio-
marker of inflammation [33]. Additionally, there are consid-
erations for miR-21 regulating apoptosis and mediating an
anti-inflammatory response in macrophages [34,35].
In plasma of people with RA, miR-24 levels were shown to
be significantly higher in comparison to healthy individuals,
while also correlating with disease activity (i.e. DAS28-CRP
and DAS28-ESR) [36] and ACPA [12,36]. ACPA is often
(but not always) detected before the development of RA [37].
Therefore, in ACPA-negative people there could be some util-
ity for assessing miRNA in RA diagnosis [12], because tradi-
tional techniques might not result in early diagnosis.
In healthy adults, miR-132 is activated by Th17 cells and
enhances osteoclastogenesis by the downregulation of
cyclooxygenase-2 transcription [38]. Conversely, in periph-
eral blood mononuclear cells from persons with RA, miR-132
expression levels are markedly higher, whereas concentrations
of miR-132 in RA plasma are lower than in healthy individu-
als [22]. Interestingly, miR-132 levels were inversely corre-
lated with tender joint count, and its role in systemic
processes as a result of joint inflammation in RA has also
been postulated [31].
miR-146a is one of the most extensively studied miRNAs in
RA [12]. It has been shown to suppress nuclear factor kappa
beta activity [39] and, in turn, suppress the inflammatory re-
sponse [40–42]. Additionally, miR-146a targets TNF
receptor-associated factor 6 (TRAF6) and IL-1 receptor-asso-
ciated kinase 1 (IRAK1), two key molecules in Toll-like recep-
tors and IL-1 signalling pathways [15]. However, in RA there
is an absence of TRAF6 and IRAK1 regulation by miR-146a,
which could contribute to the sustained production of TNF-a
and thus amplify inflammation [22]. miR-146 expression is
low in people with RA [30,32] and is inversely correlated
with CRP, ESR and TNF-alevels [12].
Expression of miR-155 is commonly increased in persons
with RA vs healthy individuals [12,43]. miR-155 is a potent
regulator of the expression of cytokines [12], such as IL-1b,
IL-6, IL-8 and TNF-a, while downregulating IL-10 produc-
tion [44]. Subsequently, miR-155 expression in persons with
RA has been positively correlated with IL-1b, TNF-a, CRP,
ESR and DAS28 [45,46]. Furthermore, miR-155 has a pleio-
tropic function and might regulate various signalling path-
ways related to the development of RA [19,44,45].
Decreased miR-221 expression is inversely associated with
circulating levels of pro-inflammatory cytokines [47]. In RA,
miR-221 expression is upregulated, leading to increased ex-
pression of VEGF, MMP-1 and MMP-3 [47], which are medi-
ators of angiogenesis and inflammation [48]. Furthermore,
overexpression of miR-221 could enhance RA synovial fibro-
blast activation and promote resistance to apoptosis [47].
miR-222 has identical seed regions, targets the same genes
as miR-221 [49] and also affects angiogenesis and inflamma-
tion [50,51]. Its expression increases with RA disease activity
[51].
Previously, it was observed that miR-223 might regulate
the differentiation of osteoclasts, which has implications for
the joints in RA [52]. Subsequently, upregulation of miR-223
expression has been reported in people with RA [32]. High
expression of miR-223 might contribute to severe synovitis
and bone destruction [52]. Nevertheless, miR-223 expression
does not appear to be correlated with DAS28, CRP or ACPAs
in RA [21,53], but circulating cell-free miR-223 might be a
useful marker of disease activity in treatment-naı¨ve persons
with early RA [30].
MicroRNAs and exercise response
Several studies have looked at the effects of exercise on a
range of miRNAs. These are summarized below in Table 1.
2Christopher Balchin et al.
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Table 1. Studies investigating the effects of exercise on circulating microRNAs
Author Participants Exercise protocol Time points of miRNA
assessment
Changes in miRNA Key findings and
implications
Baggish et al. [54] Healthy male
competitive
rowers
(n¼14)
Cardiopulmonary exercise
testing to determine
maximum oxygen
consumption, pre- and
post-90-day training
period. Incremental
cycling using a stationary
cycle ergometer
Baseline, immediately after
and 1 h post-exercise
Pre-training: miR-21,
miR-146a, miR-221 and
miR-222 all increased
(P<0.05) post-exercise
vs baseline
Post-training: miR-146a
and miR-222 increased
(P<0.05)
Other miRNAs did not
change post-exercise
Certain miRNAs were
significantly upregulated
after exhaustive aerobic
exercise before and after
exercise training
Baggish et al. [55] Healthy male
marathon
runners
(n¼21)
Marathon run Baseline, immediately after
and 24 h post-exercise
Immediately post-exercise:
miR-1, miR-126, miR-
133a, miR-134, miR-
146a, miR-208a and
miR-499 all increased
(P<0.05). The same
miRNAs all decreased
24 h post-exercise to near
baseline levels
miRNAs associated with
inflammatory processes
(i.e. miR-146a) were
significantly upregulated
immediately post-
marathon
Potential role for circulat-
ing miRNAs as unique
markers of exercise
physiology
de Gonzalo-Calvo
et al. [56]
Healthy male
amateur run-
ners (n¼9)
10 km and marathon run Baseline, immediately after,
24 and 72 h post-exercise
Immediately post-10 km
run: miR-150 increased
(P<0.05)
Immediately post-mara-
thon: let-7d, let-7f-2,
miR-125b, miR-132,
miR-143, miR-148a,
miR-223, miR-29a,
miR-34a and miR-424
increased (all P<0.05)
Other miRNAs did not
change post-exercise
Some inflammatory
miRNAs responded to
long-distance running in
an exercise dose-depen-
dent manner, whereas
other miRNAs remained
unchanged from baseline
Exercise-induced inflam-
matory miRNA response
parallels the classical in-
flammatory cascade (e.g.
inflammatory cytokines)
Li et al. [58] Healthy male
basketball
athletes
(n¼10)
Cardiopulmonary exercise
testing to determine peak
oxygen consumption,
using a stationary cycle
ergometer
Baseline and immediately
post-exercise
Immediately post-exercise:
miR-21, miR-146a,
miR-210 and miR-221
decreased (all P<0.05)
Other miRNAs did not
change post-exercise
Potential role of circulating
miRNAs reflecting the
inflammatory responses
post-acute exercise
CRF: cardiorespiratory fitness; hs-CRP: high sensitivity CRP; miR or miRNA: microRNA.
Regulation by microRNAs in RA 3
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It appears that acute exercise impacts certain circulating
miRNAs, and the response is dose dependent. However, the
type of miRNA response to exercise as summarized in Table 1
varies significantly; for example, three studies identified that
certain miRNA levels were upregulated immediately post-
exercise [54–56], whereas two studies found that miRNA lev-
els were downregulated at the same time point [57,58].
Baggish et al. [54] examined the profiles of circulating
miRNAs involved in various physiological processes, such as
inflammation (miR-21 [59] and miR-146a [15]) and angio-
genesis (miR-221 and miR-222 [60,61]), both of which are
associated with RA pathology. miRNA expression was mea-
sured at rest and after an acute bout of exhaustive cycling ex-
ercise in competitive male rowers before and after 90 days of
aerobic training. Their findings demonstrated that certain cir-
culating miRNAs were significantly upregulated after exhaus-
tive exercise. The rapid upregulation of circulating miRNAs
post-exercise could be explained by rapid increases in the cel-
lular secretion or excretion of intracellular miRNA.
Furthermore, miR-146a appears to alter the expression [62]
of CD80 [63] and glucose transporter 3 [64], which are im-
portant to the inflammatory response and, subsequently,
downregulated during acute exercise. Therefore, miR-146a
could be involved in the anti-inflammatory processes exerted
by exercise. Interestingly, they also observed a significant cor-
relation between peak exercise miR-146a level and maximum
oxygen consumption, which suggests that miR-146a could be
a plasma-based marker of cardiorespiratory fitness.
In contrast, when Nielsen et al. [57] examined miRNA ex-
pression in response to acute exercise, they found that circu-
lating miR-146a and miR-221 were downregulated
immediately post-exercise, while there was no effect on miR-
21 expression. The discrepancies could be explained by differ-
ent acute exercise bouts, because participants in the study by
Nielsen et al. [57] completed 1 h of cycling exercise at 65% of
maximum power, whereas Baggish et al. [54] used a maxi-
mum oxygen consumption cycling protocol. Additionally,
Nielsen et al. [57] used a different method when post-
processing miRNA samples. Importantly, however, it appears
that the observed increases in muscle-specific miRNAs were
attributable to selective secretion rather than generalized pas-
sive release caused by exercise-induced muscle damage [57].
Li et al. [58] conducted peak oxygen consumption assess-
ments using a cycle ergometer to investigate the miRNA re-
sponse. They also found that certain miRNAs (i.e. miR-21,
miR-146a and miR-221) were downregulated immediately
post-exercise. The authors suggested that the decrease of these
miRNAs might reflect the initial pro-inflammatory processes
that accompany acute exercise, particularly at higher intensi-
ty.de Gonzalo-Calvo et al. [56] evaluated the response of cir-
culating inflammatory miRNAs to different doses of acute
aerobic exercise. Only miR-150 levels increased significantly
after a 10 km race, whereas significant increases were ob-
served in 12 miRNAs immediately after a marathon, with all
levels returning to basal values 24 h post-race. The authors
suggested that running a marathon is associated with major
inflammatory stress, which might explain the increased ex-
pression of certain miRNAs. They also identified that inflam-
matory mediators such as IL-6, IL-8, IL-10 and hs-CRP all
increased significantly after the marathon, and the circulating
miRNA response post-exercise paralleled the inflammatory
response. This indicated a dose-dependent effect of aerobic
exercise on miRNA expression and systemic inflammation.
Furthermore, the miRNA expression pattern observed after
the marathon had predominantly anti-inflammatory effects,
which might contribute to the exercise-induced anti-inflam-
matory response. An association has been found between
miRNA activity and cytokine synthesis among healthy adults
[65]. It has also been postulated that increased anti-
inflammatory IL-6 levels post-exercise might be the result of
increased miRNA activity, which implies a possible reciprocal
relationship between miRNA and inflammation in healthy
individuals [56]. However, this mechanism requires further
investigation, particularly among people with RA.
In the only study to have looked at resistance exercise,
Sawada et al. [66] recruited 12 males, who performed a resis-
tance exercise session (consisting of bench press and leg press,
five sets of 10 repetitions at 70% of one-repetition maxi-
mum). They found that 3 days after resistance exercise the
miR-149 expression increased, whereas miR-146a and miR-
221 expression decreased. A downregulation of circulating
miR-146a and miR-221 contrasts with the findings from pre-
vious aerobic exercise studies [54,55,57]. Each exercise acti-
vates specific, and sometimes different, signalling pathways
and subsets of genes transcriptionally regulated by miRNAs
[67]. It is not clear whether circulating miRNAs are generated
in skeletal muscle or other tissues post-exercise [66]. What is
apparent is that post-exercise changes in miRNA expression
can depend on the exercise mode, intensity and duration.
Nevertheless, the collective findings indicate that miRNAs
regulate several processes relevant to physiological exercise
adaptations.
Importantly, no previous research has examined the impact
of acute exercise on miRNA expression in RA, and only one
study has investigated long-term effects of exercise on
miRNAs. O
¨zcan et al. [68] explored the effects of an exercise
training programme in people with RA (n¼30) compared
with a healthy control group (n¼30). People with RA com-
pleted strengthening and stretching exercises 2 days a week as
part of an 8-week training programme. There was no differ-
ence between groups for miR-16 and miR-155 expression,
and miR-146a expression was not affected by training.
Summary and future directions
To summarize, miRNAs play a significant role in the develop-
ment and progression of RA primarily by regulating the im-
mune and inflammatory process. They might prove to be
useful biomarkers of RA and help with early diagnosis, opti-
mization of disease management and characterization of drug
responses. This might prove important, particularly for peo-
ple with difficult-to-treat RA. Nevertheless, there is a need to
examine the downstream effects of miRNA changes on the ex-
pression of specific proteins, inflammation and disease char-
acteristics inherent in RA. Furthermore, examining these
effects in a population characterized by high-grade systemic
inflammation might increase our understanding of the role of
miRNAs in the regulation of biological processes even in the
general population.
Exercise seems to affect miRNAs, but at the moment there
is very little information in people with RA. However, there is
limited understanding of the mechanistic role of miRNAs in
exercise in people with RA. Furthermore, the evidence from
the general population is conflicting, and no precise conclu-
sions can be drawn on the specific mechanisms that miRNAs
affect. Overall, miRNAs seem to regulate several of the
4Christopher Balchin et al.
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adaptations induced by exercise, including muscle hypertro-
phy, cardiovascular fitness and angiogenesis. Exercise dose,
but also individual variation, seem to affect their levels after
an exercise session. Understanding the interaction of RA and
exercise and their combined effects on miRNAs would allow
for better planning of exercise programmes, evaluation of
exercise-related benefits or risks and even optimization of dis-
ease management. Therefore, further research in the RA pop-
ulation investigating different exercises, doses and the role of
miRNAs is required.
Data availability
No new data were generated in support of this manuscript.
Funding
C.B. received a PhD bursary from Leeds Beckett University.
No other specific funding was received from any bodies in the
public, commercial or not-for-profit sectors to carry out the
work described in this article.
Disclosure statement: The authors have declared no conflicts
of interest.
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