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REVIEW
published: 23 February 2018
doi: 10.3389/fphys.2018.00112
Frontiers in Physiology | www.frontiersin.org 1February 2018 | Volume 9 | Article 112
Edited by:
Alexandrina Ferreira Mendes,
University of Coimbra, Portugal
Reviewed by:
Oreste Gualillo,
Servicio Gallego de Salud, Spain
Francis Berenbaum,
Université Pierre et Marie Curie,
France
Tom Appleton,
University of Western Ontario, Canada
*Correspondence:
David A. Hart
hartd@ucalgary.ca
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This article was submitted to
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Frontiers in Physiology
Received: 30 October 2017
Accepted: 05 February 2018
Published: 23 February 2018
Citation:
Collins KH, Herzog W, MacDonald GZ,
Reimer RA, Rios JL, Smith IC,
Zernicke RF and Hart DA (2018)
Obesity, Metabolic Syndrome, and
Musculoskeletal Disease: Common
Inflammatory Pathways Suggest a
Central Role for Loss of Muscle
Integrity. Front. Physiol. 9:112.
doi: 10.3389/fphys.2018.00112
Obesity, Metabolic Syndrome, and
Musculoskeletal Disease: Common
Inflammatory Pathways Suggest a
Central Role for Loss of Muscle
Integrity
Kelsey H. Collins 1,2 , Walter Herzog 1,2, Graham Z. MacDonald 1, Raylene A. Reimer 1, 3,
Jaqueline L. Rios 1,2,4 , Ian C. Smith 1, Ronald F. Zernicke 1, 5,6 and David A. Hart 1, 2,7,8
*
1Human Performance Laboratory, Faculty of Kinesiology, University of Calgary, Calgary, AB, Canada, 2McCaig Institute for
Bone and Joint Health, University of Calgary, Calgary, AB, Canada, 3Department of Biochemistry and Molecular Biology,
University of Calgary, Calgary, AB, Canada, 4CAPES Foundation, Brasilia, Brazil, 5Departments of Orthopaedic Surgery and
Biomedical Engineering, School of Kinesiology, University of Michigan, Ann Arbor, MI, United States, 6Department of Surgery,
Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada, 7Department of Family Practice,
The Centre for Hip Health and Mobility, University of British Columbia, Vancouver, BC, Canada, 8Alberta Health Services
Bone and Joint Health Strategic Clinical Network, Calgary, AB, Canada
Inflammation can arise in response to a variety of stimuli, including infectious agents,
tissue injury, autoimmune diseases, and obesity. Some of these responses are acute
and resolve, while others become chronic and exert a sustained impact on the host,
systemically, or locally. Obesity is now recognized as a chronic low-grade, systemic
inflammatory state that predisposes to other chronic conditions including metabolic
syndrome (MetS). Although obesity has received considerable attention regarding its
pathophysiological link to chronic cardiovascular conditions and type 2 diabetes, the
musculoskeletal (MSK) complications (i.e., muscle, bone, tendon, and joints) that result
from obesity-associated metabolic disturbances are less frequently interrogated. As
musculoskeletal diseases can lead to the worsening of MetS, this underscores the
imminent need to understand the cause and effect relations between the two, and the
convergence between inflammatory pathways that contribute to MSK damage. Muscle
mass is a key predictor of longevity in older adults, and obesity-induced sarcopenia is a
significant risk factor for adverse health outcomes. Muscle is highly plastic, undergoes
regular remodeling, and is responsible for the majority of total body glucose utilization,
which when impaired leads to insulin resistance. Furthermore, impaired muscle integrity,
defined as persistent muscle loss, intramuscular lipid accumulation, or connective tissue
deposition, is a hallmark of metabolic dysfunction. In fact, many common inflammatory
pathways have been implicated in the pathogenesis of the interrelated tissues of the
musculoskeletal system (e.g., tendinopathy, osteoporosis, and osteoarthritis). Despite
these similarities, these diseases are rarely evaluated in a comprehensive manner. The
aim of this review is to summarize the common pathways that lead to musculoskeletal
damage and disease that result from and contribute to MetS. We propose the
overarching hypothesis that there is a central role for muscle damage with chronic
Collins et al. Obesity, MetS, and Musculoskeletal Disease
exposure to an obesity-inducing diet. The inflammatory consequence of diet and muscle
dysregulation can result in dysregulated tissue repair and an imbalance toward negative
adaptation, resulting in regulatory failure and other musculoskeletal tissue damage. The
commonalities support the conclusion that musculoskeletal pathology with MetS should
be evaluated in a comprehensive and integrated manner to understand risk for other
MSK-related conditions. Implications for conservative management strategies to regulate
MetS are discussed, as are future research opportunities.
Keywords: joint diseases, muscle, bone, tendon, NFkB, MAPK
METHODOLOGY
The studies presented in this review were identified through
PubMed Searches and the review of relevant papers in the area
of diet-induced obesity, musculoskeletal health, musculoskeletal
disease, and inflammation.
INTRODUCTION TO METABOLIC
SYNDROME AND OBESITY
Metabolic syndrome (MetS) is a cluster of conditions—
visceral obesity, hypertension, dyslipidemia, and elevated fasting
glucose—that increase an individual’s risk for diabetes and
cardiovascular complications (Alberti and Zimmet, 1998; Manuel
et al., 2014). Human metabolism has evolved to efficiently
convert chemical energy obtained through the consumption of
food into thermal and chemical energy. Our body’s metabolic
pathways have developed to provide energy to tissues in times
of physical threat and survival, or to efficiently conserve energy
in times of food deprivation. Today, westernized societies have
an abundance of food (food security) and many individuals have
little need to perform physical activity. This combination has led
to excessive nutrient storage, placing significant stress on our
metabolic pathways, and leading to an increase in the prevalence
of disease stemming from metabolic dysfunction (Miranda et al.,
2005).
Concordant with the rise in MetS prevalence, there is also
a global increase in the prevalence of musculoskeletal (MSK)
diseases and disorders (Wearing et al., 2006). Recent evidence
demonstrates that metabolic complications also increase the
risk for the most prominent MSK diseases, such as sarcopenic
obesity (muscle loss in obesity), osteoporosis, tendinopathy,
and osteoarthritis, conditions which contribute significantly to
disability and time lost from work. The resultant damage and
pain associated with these conditions likely develops through
low-level systemic inflammation (Hoy et al., 2014; Smith et al.,
2014;Figure 1) in addition to loading due to obesity (Felson
et al., 1988), and reduced ability to withstand loading due to
sarcopenia.
MSK disease is of particular concern, for example, as
osteoarthritis-related walking disability significantly increases
risk for all-cause mortality and cardiovascular events, when
controlling for other cofounders (Hawker et al., 2014). This
suggests that MSK disability associated with MetS can contribute
to the worsening of MetS through sedentary behavior. Although
obesity has received considerable attention regarding chronic
cardiovascular conditions and diseases, as well as diabetes, the
MSK complications that result from obesity associated MetS are
less frequently discussed and rarely evaluated comprehensively.
Muscle mass is a key predictor of longevity in older adults
(Srikanthan and Karlamangla, 2014), and since muscle is highly
plastic and undergoes regular remodeling, it is a vulnerable
tissue in a chronic low-level inflammatory environment, such
as that seen with metabolic dysfunction (Tidball, 2005; Fink
et al., 2014; D’Souza et al., 2015; Collins et al., 2016a). For
example, intramuscular lipid deposits increase with obesity and
are also positively correlated with insulin resistance (Akhmedov
and Berdeaux, 2013; Addison et al., 2014; Fellner et al., 2014),
linking structural alterations with altered capacity for glucose
homeostasis. Functionally, impaired muscle integrity, persistent
atrophy, and lipid accumulation in muscle are risk factors for
tendinopathy (Meyer and Ward, 2016), osteoporosis (Ormsbee
et al., 2014), osteoarthritis (Lee et al., 2012), and integrity of a
motion segment, such as the leg (Figure 2).
A ROLE FOR METABOLIC DISTURBANCE
IN MOTION SEGMENT TISSUE DAMAGE
A hypothesis has emerged proposing that metabolically mediated
damage to MSK tissues may be one additional component of
the MetS, as adipose-based inflammation links obesity, MetS,
and MSK tissue damage (Hart and Scott, 2012; Zhuo et al.,
2012). Increased visceral adiposity is linked to induction of
increased levels of catabolic mediators (Fontana et al., 2007)
and ultimately tissue damage (Figures 1 –3). Additionally, the
presence of hypertension may be linked to tissue damage through
vasoconstriction and ultimately depriving tissues of appropriate
nutrient exchange (McMaster et al., 2015). Moreover, high
cholesterol is speculated to link dysregulated lipid metabolism
and endothelial dysfunction and has been directly associated
with tissue damage in tendons (Tilley et al., 2015), decreased
bone mineral density (Makovey et al., 2009), and osteoarthritis
damage (Farnaghi et al., 2017). In parallel, investigations into
the impact of low-level systemic inflammation from metabolic
disturbance on the onset of sarcopenic obesity tendinopathy,
osteoporosis, and osteoarthritis have been conducted. Many of
these authors report associations between low-level systemic
inflammation from diet-induced obesity (DIO) with MSK disease
outcomes (Table 1), however these diseases are seldom evaluated
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Collins et al. Obesity, MetS, and Musculoskeletal Disease
FIGURE 1 | The interface between metabolic complications and musculoskeletal compromise.
comprehensively to evaluate a common inflammatory pathway
to disease induction and progression.
As such, we suggest a hypothesis linking altered muscle
integrity to direct and indirect consequences on the motion
segment (Figures 2,3). An obesogenic diet, resulting in over
nutrition and development of a low-level systemic inflammation,
acutely challenges associated tissues of the motion segment
and can result in positive adaptation (i.e., through dynamic
compensation that helps the tissue accommodate metabolic
challenge), as well as negative adaptation (i.e., vulnerability
to deleterious changes in tissue integrity). With these initial
challenges, such tissue adaptive responses are balanced and help
preserve the associated tissues and motion segment integrity.
However, with chronic exposure to obesogenic diet and its
inflammatory consequences, tissues demonstrate dysregulated
repair, an imbalance toward negative adaptation resulting in
regulatory failure, tissue damage (i.e., ectopic lipid storage
and tissue fibrosis), and failure of motion segment integrity
progressing to loss of function and ultimately, disease.
AIM AND SCOPE OF REVIEW
The aim of this review is to summarize the links between
induction of local and systemic inflammation, DIO, and a central
role for muscle integrity in the inflammation-based pathogenesis
of these MSK diseases. Early loss of muscle integrity can have
both direct and indirect “ripple” effects downstream on tendons
and bones, as well as the functioning of multi-tissue complex
joints (e.g., the joint as an organ, Figure 2) (Frank et al.,
2004; Loeser et al., 2012). As muscle plays a critical role in
the mechanical and biological homeostasis of bones (through
the muscle tendon unit indirectly and directly through the
muscle/bone interface), tendons (directly through the muscle
tendon unit), and joints (through loading and stabilization), we
suggest that with the influence of dysregulated muscle loading,
inflammation, and altered muscle integrity, failure of motion
segment integrity is induced and exacerbated.
This review is focused on outcomes from studies using pre-
clinical DIO models, as the gradual and progressive pathway
toward MetS afforded by DIO provides critical insight into
the short- and long-term pathophysiology, in addition to the
phenotype of MSK diseases (Buettner et al., 2007; Nilsson et al.,
2012). Evaluating diet-induced alterations allows for linking
results across systems from food, through the gut and the
associated microbiome, to early and late tissue-based changes, as
well as the inclusion of potential epigenetic outcomes regarding
temporal relations for the onset and progression of MSK disease.
OBESITY AND IMPACT ON MUSCLE
INTEGRITY
Sarcopenic Obesity
Sarcopenic obesity, or low muscle mass and quality with
increased fat mass, is not only associated with poor physical
function (Zamboni et al., 2008), but also results in additional
weight gain and an 8 to 11-fold increase in the risk for three
or more additional physical disabilities (Baumgartner, 2000).
Sarcopenic obesity was first defined clinically using two criteria:
(a) an individual who is −2 standard deviations in muscle
mass index (muscle mass/height2) compared to healthy, same-
sex younger individuals; and (b) an individual who has a body
fat percentage greater than the median body fat percentage for
each sex (males: muscle mass index <7.26 kg/m2with body fat
percentage >27%, females: muscle mass index <5.45 kg/m2body
fat percentage >38%) (Baumgartner et al., 1998; Baumgartner,
2000). An alternative criteria for sarcopenic obesity involves
falling below a linear regression-based threshold amount of lean
mass given an amount of fat mass (Stenholm et al., 2008).
Sarcopenic obesity can predict disability and loss of activity
in elderly adults (Baumgartner et al., 2004), and sarcopenic
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Collins et al. Obesity, MetS, and Musculoskeletal Disease
FIGURE 2 | Potential impact of changes in muscle damage on lower limb motion segment integrity.
obesity is more closely associated with MetS than either obesity
or sarcopenia alone. This suggests important roles for both fat
accumulation and muscle loss in the etiology of MetS (Lim
et al., 2010). Although the age-dependent declines in muscle
structure and strength are well-documented, the mechanism
by which MetS results in sarcopenic obesity remains to be
clarified (Kob et al., 2014). As sarcopenic obesity results in
disability, loss of activity, altered mechanical loading, and
altered biological function in the muscle due to lipid deposition
and its sequelae (Ormsbee et al., 2014), it is likely that
sarcopenic obesity is central to the development of other
musculoskeletal pathologies. In fact, data from our laboratory
in a rat model revealed changes in the integrity of specific
muscles as early as 3-days on a high-fat/high-sucrose (HFS)
diet (Collins et al., 2016c), and correspond to long-term
changes in systemic inflammation and gut microbiota (Collins
et al., 2015a). These data support the notion that muscle
may be among the first MSK tissues affected by DIO, and
inflammation likely plays a substantial role in this loss of
integrity.
Dysregulated Tissue Regeneration of
Muscle—Primary Tissue Damaged by MetS
Muscle fiber damage happens on a daily basis and is generally
considered to be a beneficial stimulus, leading to growth and
adaptation through muscle regenerative processes (Karalaki et al.,
2009). In muscle, monocyte and macrophage recruitment, as
well as phagocytosis of necrotic material, occurs within the
first 24 hours. Muscle is repaired through a series of tightly-
controlled inflammatory processes (Akhmedov and Berdeaux,
2013). Specifically, muscle regeneration is a multistep process
involving degeneration, regeneration, and remodeling, ultimately
restoring structure and function (Laumonier and Menetrey,
2016).
The three most active cells in the regeneration of skeletal
muscle are macrophages, satellite cells, and fibroblasts
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Collins et al. Obesity, MetS, and Musculoskeletal Disease
FIGURE 3 | Structural and inflammatory changes in muscle with obesity; (A) factors that influence muscle structural integrity with metabolic challenge; (B) alterations
in adipose tissue; (C) musculoskeletal consequences of chronic-low grade inflammation.
(Akhmedov and Berdeaux, 2013). The metabolic complications
associated with obesity can result in an inappropriate temporal
recruitment of these cells, which in turn leads to impaired
angiogenesis and myocyte formation, while promoting the
deposition of fibrotic and adipose tissue, ultimately leading to
a reduction in structural integrity and functional capacity of a
muscle (Karalaki et al., 2009).
With DIO, metabolic dysfunction and the presence of chronic
low level inflammation can impair the “normal” inflammatory
response and the regenerative capacities of skeletal muscles,
resulting in a pseudo-injury (Collins et al., 2016c;Figure 3).
For example, elevated levels of leptin, a satiety hormone now
appreciated to have a role in low-level systemic inflammation,
can impair angiogenesis, leading to tissue ischemia (Brown et al.,
2015). IL-6 expression at the muscle level is a key mediator
of macrophage infiltration and muscle repair (Zhang et al.,
2013), while elevated expression of TGF-βpromotes an increased
fibrotic tissue deposition (Laumonier and Menetrey, 2016).
Efficient muscle regeneration can be attributed to satellite
cells being readily available, and the cells’ ability to re-establish
residual pools to support multiple rounds of regeneration
(Karalaki et al., 2009). Satellite cells are limited by the
complex physiological environment in which they interact, an
environment that can be significantly altered in individuals with
obesity (D’Souza et al., 2015). A pathological host environment
can limit a satellite cell’s ability to be activated, proliferate, and
differentiate into a muscle fiber (D’Souza et al., 2015; Meng
et al., 2015). This was elegantly shown by Boldrin and colleagues
through the transplantation of satellite cells from mdx mice,
a genetic mouse model of muscular dystrophy, into a neutral
environment (Boldrin et al., 2015). Despite the impairment
of mdx satellite cells as a result of being in the pathogenic
environment of an mdx mouse, following transplantation, mdx
satellite cells were fully capable of being activated, and could
proliferate and differentiate into a fully functional muscle fiber
(Boldrin et al., 2015). Macrophages may also inhibit satellite
cell activity, suggesting another mechanism by which low-level
systemic inflammation may inhibit muscle repair (Tidball and
Villalta, 2010).
Impairments in satellite cell activity have been reported to
promote fibro/adipogenic progenitor cells (FAP) that normally
aid in muscle regeneration, to differentiate into fibroblasts
and/or adipocytes (Chapman et al., 2016). FAPs have also been
demonstrated to be a source of intramuscular lipid deposition
with rotator cuff/supraspinatus tendon injury (Liu et al., 2016).
FAPs are thought to be vulnerable to reprogramming in
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Collins et al. Obesity, MetS, and Musculoskeletal Disease
TABLE 1 | Examples of MSK damage resulting from DIO.
Species Strain Experimental diet MSK changes observed due to DIO Authors Year
Mouse C57b6 60% Fat Quadriceps muscle macrophages—short
term
Fink 2014
Quadriceps muscle macrophages Patsouris 2008
Metabolic knee OA Griffin 2012
Decreased tendon failure stress load Grewal 2014
Decrease in bone quality and quantity Ionova-Martin 2010
Mouse C57b6 40% Fat Increased macrophages in soleus muscle Nguyen 2007
Mouse C57b6 45% Fat Decreased cancellous bone mass Cao 2009
Mouse C57b6 10% Corn oil Osteoporosis outcomes Halade 2010
Mouse C57b6 45% Fat, 40% Sucrose Decreased BMD, uCT and osteoporosis
outcomes
Bhatta 2016
Adverse effect on bone morphology and
mechanics
Lorincz 2010
Rat Sprague dawley 40–45% Fat, 45–40% Sucrose Compromised vastus lateralis muscle
integrity in 3-days
Collins 2016
Fibrosis and lipid deposition in VL Collins 2016
Metabolic knee OA Collins 2015a, 2015b, 2016, 2017a
Rabbit New Zealand white 50% Fat Increased metabolic knee OA Brunner 2012
1% Cholesterol, 3% Peanut oil Increased knee joint tissue damage Prieto-Potin 2013
Pig Ossabaw 20% Fructose, 46% Fat, 20%
Fructose, 2% Cholesterol
Muscle damage Clark 2011
Monkey Rhesus 42% Fat, 27% sucrose Muscle myosin heavy chain transition from
oxidative to glycolytic isoforms
Hyatt 2016
the presence of low-level inflammation, which may result in
increased lipid and fibrosis deposition, and may limit reversibility
of fibrosis (Mann et al., 2011). Thus, chronic obesity and
associated MetS, with inflammation and fatty infiltration of
muscles, may lead to a compromise in the regeneration of muscle
integrity.
In addition to the environmental challenges to the muscle
regeneration posed by metabolic disturbance, skeletal muscle
from individuals with obesity displays a greater number
of glycolytic-fibers vs. oxidative-fibers when compared to a
healthy individual (Pattanakuhar et al., 2017). Since oxidative-
fibers generally contain a greater number of satellite cells
relative to glycolytic fibers (Karalaki et al., 2009), individuals
with obesity may also have fewer satellite cells. Based on
this information, impairments in satellite cell function as a
result of alterations in cell metabolism, a reduction in cell
number, suppression of cell activation, depleted cell reserves,
and impaired cell proliferation and differentiation may lead
to impairments in muscle fiber regeneration (Akhmedov and
Berdeaux, 2013).
Work from our laboratory has demonstrated that the
oxidative soleus muscle is protected against HFS-induced
damage over short-term and long-term exposures in a rat model
(Collins et al., 2017b;Figure 4). By 3-days on HFS, dynamic
increases in mRNA levels for superoxide dismutase (SOD2) in
HFS animals implicate compensatory oxidative stress scavenging
in the soleus muscle compared to control animals. By 2-
weeks on HFS, increased mRNA levels for oxidative capacity
[succinate dehydrogenase (SDH)] were detected compared
to chow-fed controls, suggesting one adaptation strategy
that the soleus muscle may employ with HFS metabolic
challenge. Although the precise mechanism(s) by which the
soleus is protected from metabolic disturbance-induced muscle
damage remains to be clarified, it appears that increasing the
oxidative capacity and the oxidative stress scavenging ability
of muscles (i.e., with aerobic exercise) may be a beneficial
strategy for mitigating obesity-induced muscle damage and its
consequences.
Inflammation related to obesity can also impair myocyte
remodeling as a result of a reduction in protein synthesis due to
elevated TNF-αlevels (Brown et al., 2015). Furthermore, there
is evidence for adipocyte-muscle cross talk in vitro, whereby
adipocyte-derived inflammation can contribute to inflammation
and atrophy in muscle cells subjected to a metabolically
dysfunctional environment, possibly through IGF-1 (Pellegrinelli
et al., 2015). Impaired protein synthesis can also prevent muscle
from properly adapting to mechanical stimuli. Brown et al. (2015)
demonstrated this inability, showing that following muscle
damage, obese muscle displayed no adaptations, while lean
mice displayed an increase in muscle wet weight and muscle
fiber hypertrophy (Brown et al., 2015). Potential contributing
factors to a reduction in protein synthesis may be elevated
lipid metabolites resulting from impaired mitochondrial function
contributing to elevated TNF-αlevels, which are known to have
inhibitory effects on IGF-1 (Akhmedov and Berdeaux, 2013).
Decreases in IGF-1 result in the inhibition of the muscle growth
signaling pathway (IGF-1 →P13K →Akt →mTOR),
effectively blunting muscle protein synthesis (Brown et al., 2015).
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Collins et al. Obesity, MetS, and Musculoskeletal Disease
FIGURE 4 | Vulnerability and protection of muscle with diet-induced obesity may be determined by oxidative capacity; (A) system level changes; (B) tissue-level
changes; (C) cellular and molecular level alterations.
Furthermore, increased myostatin levels can also contribute
to impaired growth in obese muscle. Myostatin is not only
significantly up-regulated in obese skeletal muscle, but in adipose
tissue as well, further inhibiting myogenesis, providing another
avenue through which potential muscle-adipose cross talk may
occur (Karalaki et al., 2009).
Functional Muscle Damage with Metabolic
Derangement
Generally speaking, adults with obesity are reported to have
significantly higher absolute strength in lower limb muscles,
but lower strength when normalized to body mass (Tomlinson
et al., 2016). When the upper limb muscles are evaluated,
there are no statistical significant differences between individuals
with obesity and normal-weight controls (Tomlinson et al.,
2016). Potentially, the characterization of obesity by body mass,
which is common in these studies, may be inappropriately
representing body composition. We have shown, in a healthy
and overweight population cohort, that body mass index (BMI)
inappropriately estimates body composition in 30% of the
population, with a specific disparity between BMI and body
composition measurements in healthy females (Collins et al.,
2017c). Also, there is a lack of data describing the effect of obesity
on muscle integrity, and a lack of consistent protocols to assess
muscle strength (Tomlinson et al., 2016). However, data from
our lab (Collins et al., 2016a,c, 2017b) and others, in rodents
(Ciapaite et al., 2015) and large mammals (Clark et al., 2011),
have demonstrated deleterious alterations in muscle structural
integrity with metabolic disturbance. Computational approaches
modeling the gastrocnemius muscle have demonstrated that
whole-muscle force is dependent on muscle integrity, specifically
regarding reductions of muscle force due to intramuscular
lipid (Rahemi et al., 2015). A zebrafish model of diet-induced
obesity further demonstrated that obesity induces decreases in
locomotor performance, isolated muscle isometric stress, work-
loop power output, and muscle relaxation rates (Seebacher et al.,
2017). Of note, these decrements in performance and function
were not reversed with weight loss, generating interesting
questions about the potential reversibility of impaired muscle
function with obesity.
Additional sources of muscle damage and altered repair are
advanced glycation end products (AGEs), which accumulate over
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Collins et al. Obesity, MetS, and Musculoskeletal Disease
time due to increased availability of glucose and hyperglycemia
(Figure 5). Dietary AGEs can interfere with muscle healing and
impair contractile function in a mouse model of obesity (Egawa
et al., 2017). HFS diets can induce hyperglycemia in rodents,
further linking diet-induced obesity to AGEs (Sumiyoshi et al.,
2006). The receptor for AGEs on macrophages, called RAGE,
is associated with a pro-inflammatory state, and RAGE/AGEs
are reported to be involved in the onset and progression
of metabolic disturbance, insulin resistance, and adipokine
expression (Leuner et al., 2012; Hofmann et al., 2014). AGEs
have been implicated in macrophage polarization toward M1
pro-inflammatory phenotypes, pro-inflammatory IL-6 secretion
in adipose tissues, and initiating inflammatory cascades (Bopp
et al., 2008; Frommhold et al., 2011; Nativel et al., 2013; Jin et al.,
2015; Son et al., 2016) [i.e., NF-κB, p38 mitogen-activated protein
kinase (MAPK)]. Reactive AGEs can also cross-link with collagen
fibers, which subsequently can affect the fiber’s mechanical and
biological properties (Abate et al., 2013). Although AGE collagen
cross-linking can be reversed (Asif et al., 2000), it is unclear
whether glycation itself can be reversed. Of note, endurance
exercise has been shown to attenuate AGEs in cardiac muscle of
rats (Wright et al., 2014).With weight loss, reversal of metabolic
dysfunction may not be fully achievable, and weight re-gain is
common (Fothergill et al., 2016). As mentioned above, to what
degree reversibility of skeletal muscle damage may be achieved
in this context remains to be determined (Figures 2 –4), and
several factors could contribute to irreversibility (Mann et al.,
2011). Likely, clarifying relations between the time of exposure
to low-level systemic inflammation and muscle damage should
be determined, as impaired muscle integrity has been observed
following short-term exposure to a metabolic challenge, likely
before “full” metabolic derangement has been achieved (Fink
et al., 2014; Collins et al., 2016c). Also, some alterations in
satellite cell function can be irreversible (Sacco and Puri, 2015).
Generally, DNA methylation, or epigenetic changes, is an actively
researched area being explored in the context of muscle (Carrió
and Suelves, 2015), and DNA methylation is an important step
in muscle cell differentiation (Brunk et al., 1996). However, it is
likely that epigenetic changes, which are dynamic and induced by
environmental changes, can induce cellular reprogramming, and
thus could potentially limit the reversibility of muscle damage,
even if the MetS-related inflammation is controlled (Carrió and
Suelves, 2015). Investigations to clarify the role of methylation
in physiological and pathophysiological muscle changes may
provide valuable insight into the reversibility potential of muscle
damage.
Dysregulated Homeostasis of Associated
Motion Segment Tissues (Tendon, Bone,
Cartilage, and Joint) with Obesity: Acute
and Chronic
Muscle, tendon, cartilage, and bone tissues repair and regenerate
over different timelines, and these different repair timelines may
dictate vulnerability or resistance to damage with metabolic
disturbance involving inflammatory processes. Both biological
and mechanical stimuli are critical to homeostatic tissue
regulatory mechanisms. Across tissues, remodeling rates slow
FIGURE 5 | Interacting variables reinforcing metabolic dysfunction and sequelae.Links between dietary sugar, dietary saturated fat, increased hyperglycaemia,
advanced glycation end products (AGEs), their receptors (RAGEs), and inflammation, macrophage polarization, and collagen cross-linking.
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Collins et al. Obesity, MetS, and Musculoskeletal Disease
with age. As discussed above, muscle tissue is likely the most
vulnerable MSK tissue to perturbation with metabolic challenge.
Repair of such tissues in the face of an active inflammatory
environment is likely compromised, and resolution of repair is
particularly challenging (Hart et al., 2004).
Altered muscle integrity can challenge the motion segment in
a dynamic manner, until the associated tissues ultimately begin to
fail (Figures 2,3). Specifically, tendon healing is slower compared
to muscle. In tendon, tenocytes migrate to the wound, initiating
type III collagen synthesis. After several weeks to months,
remodeling of tendinous tissue occurs such that collagen fibers
are aligned in the direction of stress, and maturation occurs over
the course of a year. Bone mechanotransduction, initiating the
maintenance/remodeling processes (Scott et al., 2008), requires a
series of events that can require almost 24-h to ultimately result in
the synthesis of bone matrix proteins (Robling and Turner, 2009).
Cartilage is considered to have limited intrinsic repair properties,
although with the facilitation of autologous stem cells, biologics,
and other transplants, some repair may be achievable (Chu
et al., 2010). The impaired regenerative capacity of tendon, bone
and cartilage likely indicate a lack of reversibility with altered
integrity and subsequent compromise in function, underscoring
a need for strategies aimed at primary prevention (before it
occurs), secondary prevention (limiting the amount of damage
as it occurs), tertiary prevention (prevention of progression of
damage to disease), or reversal of damage.
DIET-INDUCED OBESITY AND ELEMENTS
OF THE DYSREGULATED INFLAMMATORY
RESPONSE
Inflammatory Mediator Alterations in
Obesity
Cytokines and Chemokines
Activation of the innate immune system is critical in the
pathogenesis of type 2 diabetes and tissue damage. Some of
the key signaling pathways involved in this process are nuclear
factor –κB (NF-κB), c-Jun N-terminal Kinase (JNK), and the
NLRP3 inflammasome, all resulting in transcription of pro-
inflammatory cytokines (Lackey and Olefsky, 2015). NF-κB can
be activated by elevated levels of pro-inflammatory cytokines
such as TNF-α, which is increased in the adipose tissue of
obese and diabetic animals. Neutralizing TNF-αhas been
shown to reduce insulin resistance (Hotamisligil et al., 1993).
Additionally, JNK activity increases in tissues that are sensitive
to insulin, is activated by ER stress, and directly inhibits insulin
signaling (Gual et al., 2005; Lackey and Olefsky, 2015). The
inflammasome is a protein complex that matures and secretes
inflammatory cytokines, such as IL-1βand IL-18. Similar to NF-
κB, the inflammasome can be activated by pro-inflammatory
cytokines, lipopolysaccharide (LPS), and some forms of low
density lipoproteins (LDLs). LPS, low density lipoproteins, and
the AGE-product of LDLs can signal through Toll-like Receptor-
4 (TLR-4) (Hodgkinson et al., 2008), activating IL-1βand IL-18
signaling.
TLR-4 recognition of saturated fatty acids is necessary
to enable NF-κB signaling and induce expression of pro-
inflammatory cytokines (TNF-α, IL-6, and MCP-1) (Jialal et al.,
2014; Lackey and Olefsky, 2015). TLRs sense pathogen-associated
molecular patterns and damage-associated molecular patterns
(PAMPs), and regulate the inflammatory responses to mitigate
tissue repair (Lee et al., 2013). TLR-4 gene expression and protein
content are increased in muscle from patients with obesity
and diabetes, potentially contributing to insulin resistance, as
well as compromised muscle integrity observed with metabolic
disturbance (Reyna et al., 2008). In the context of OA, TLRs can
modulate the catabolic pathways and maintain joint homeostasis
(Houard et al., 2013). Of interest, the lubricating molecule
proteoglycan-4 (PRG-4) has been shown to modulate the
inflammatory response through competitive inhibition of TLR-
4 receptors, suggesting that as PRG-4 concentration is reduced
with OA severity, inflammatory modulation may also be reduced,
contributing to the progression of OA (Iqbal et al., 2016). In
tendinopathy, there may not be a clear role for TLRs, as catabolic
processes in Achilles tendinopathy seem to occur independently
of TLR4-induced gene expression from IL-1βor TNF-α(de
Mos et al., 2009). In bone, LPS-induced activation of TLR-4
in neutrophils is reported to upregulate the catabolic RANKL
osteoclast cascade, linking TLR based inflammation to increased
bone resorption (Chakravarti et al., 2009).
Appropriate levels of pro-inflammatory cytokines are
necessary for tissue homeostasis. However, exogenous exposure
to pro-inflammatory cytokines, or endogenous high levels of
pro-inflammatory cytokines, are associated with damage across
all musculoskeletal tissues. In muscle, TNF-α, IL-1β, and IL-6
activate transcription of MuRF-1 and MAFBx/atrogin-1, the
key muscle atrophy pathway, through IGF/Akt-1 (Akhmedov
and Berdeaux, 2013). For example, IL-6 and TNF-αinhibit
bone-forming osteoblast cells, and NF-κb, RANKL, TNF-α, IL-6,
M-CSF, and MCP-1 can contribute to osteoclast recruitment,
maturation, and inhibit osteoclast apoptosis (Roy et al., 2016).
In tendon, pro-inflammatory cytokines (IL-1β, TNF-α, IL-6)
can disrupt tissue homeostasis, by inducing extracellular matrix
degradation, induce other pro-inflammatory cytokines, which
result in necrotic and apoptotic cell changes, and affect collagen
and elastin expression (Schulze-Tanzil et al., 2011). Cytokine
effects in tendon are modulated by mechanical loading in this
complex mechano-biological environment (Killian et al., 2012).
The knee joint is a complex organ system with many
resident inflammatory cells, particularly in the synovium and
infrapatellar fat pad. These tissues secrete pro-inflammatory
cytokines, like IL1-αand IL-1β(Sanchez-Adams et al., 2014).
In humans, systemic and synovial fluid inflammatory profiles
can differentiate between patients based on OA severity,
suggesting that cytokine levels may help define OA pathogenesis
(Heard et al., 2013). In addition to the infrapatellar fat pad,
there is also a synovial adipose depot, and these two depots
differ significantly from each other in lean individuals with
OA (Harasymowicz et al., 2017). Moreover, infrapatellar fat
pads and synovium adipose depots differed in adipocyte size,
fibrosis, and macrophage infiltration in OA patients with
obesity compared to lean OA patients (Harasymowicz et al.,
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Collins et al. Obesity, MetS, and Musculoskeletal Disease
FIGURE 6 | Markers of muscle integrity are associated with metabolic OA severity after 12-weeks of high-fat high-sucrose diet-induced obesity. (ORO, Oil Red O stain
for intramuscular fat; Picro, Picrosirius stain for collagen).
2017). High glucose concentrations can contribute to increased
chondrocyte responsiveness to cytokines, increased levels of
reactive oxygen species, leading to an overproduction of IL-6
and PGE2 (Laiguillon et al., 2015). These cytokines can also
contribute to mitochondrial dysfunction within the joint, and,
in turn, mitochondrial dysfunction can amplify chondrocyte
responsiveness to cytokines (Vaamonde-García et al., 2012).
Unpublished data from the author’s laboratories suggest
that intramuscular lipid deposits and fibrotic material in the
vastus lateralis muscle of the knee are associated with the
presence of metabolic-induced knee joint damage after a 12-week
obesity induction period (Figure 6). Based on the inflammatory
mediator profile of joints undergoing damage (Collins et al.,
2015a,b, 2016b), inflammation is likely playing a significant role
in this process and in the relations between muscle damage and
joint damage. Ongoing efforts will probe the role of associated
inflammation on muscle integrity in the onset and progression
of such metabolic joint damage and whether it leads to
overt OA.
Given the systemic-to-local hypothesis in metabolic OA
(Zhuo et al., 2012; Collins et al., 2016b; Berenbaum et al., 2017),
we have evaluated hip, knee, and shoulder joints using the HFS
rat model system for 12-weeks (Collins et al., 2017a). A HFS
diet, in the absence of trauma, resulted in significant increases
in joint damage/OA-like changes in the shoulder and knee joints
of rats after a standard 12-week obesity induction period. The
hip joint, however, was not significantly affected by DIO, which
is consistent with findings from human epidemiological studies.
Total joint damage, assessed by adding the individual Modified
Mankin Scores across all three joints, was increased in DIO
animals compared to chow-fed animals, and was associated
with the percentage of body fat. Positive significant predictive
relations for total joint score were found between body fat and
two serum mediators (IL-1αand VEGF). These data suggest
that systemic inflammatory alterations from DIO in this model
system may result in a higher incidence of knee, shoulder, and
multi-joint OA-like/joint damage with the HFS diet over the
long term (Collins et al., 2017a). Due to the preliminary nature
of these studies, longitudinal experiments with multiple time
points are needed to validate these proposed relations. If these
relations are supported in future studies, then not all joints
are affected equally by obesity-associated inflammation in MetS.
Studying these relations are an ongoing direction of current
research.
Adipokines
Adipocytes release adipokines such as leptin, adiponectin,
visfatin, and resistin as a signaling mechanism in addition
to passively storing energy, which can cause and exacerbate
chronic low-level systemic inflammation (Gomez et al., 2009).
Adipokines have been shown to induce pro-inflammatory
mediators in activated CD4+T cells from osteoarthritis patients,
demonstrating that systemic mediators may play a role in
osteoarthritis (Scotece et al., 2017). After interaction with such
activated CD4+T cells, chondrocytes demonstrate increased
expression of MMP-13 and decreased expression of collagen-2
and aggrecan.
Leptin is a satiety hormone that increases in a near-
linear fashion to body fat (Friedman and Halaas, 1998). It
inhibits appetite and regulates body weight, energy expenditure,
and maintains glucose homeostasis. However, with metabolic
disturbance, individuals become leptin resistant. Leptin is a class-
1 cytokine secreted from adipose tissue, and high concentrations
of leptin are associated with musculoskeletal tissue damage
(Zabeau et al., 2003; Collins et al., 2015a,b, 2016b,c). Leptin
activates downstream pro-inflammatory pathways (IL-2, IFNγ)
and inhibits the anti-inflammatory pathway (IL-4) (Lechler et al.,
1998). Aside from being produced by adipose tissue, leptin levels
can be increased by TNF-α, IL-1, and LPS, creating a positive-
feedback loop with low-level chronic inflammation (Grunfeld
et al., 1996).
Leptin signaling is critical to conventional muscle
maintenance (Akhmedov and Berdeaux, 2013), and basal levels
of satellite cells are reduced in animals with impaired leptin
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Collins et al. Obesity, MetS, and Musculoskeletal Disease
TABLE 2 | Differential mRNA levels for leptin, IP-10 and IL-1βwith 12- and 28-weeks of diet-induced obesity.
Length of metabolic
challenge
Infrapatellar fat pad Synovium
Leptin IP-10 IL-1βLeptin IP-10 IL-1β
12-weeks 13.9 ±3.1** 1.6 ±0.6 0.60 ±0.10 7.3 ±2.6*# 0.4 ±0.1 1.0 ±0.2
28-weeks 0.7 ±0.1 5.3 ±1.6** 2.9 ±0.6** 1.0 ±0.4 3.3 ±0.9* 0.9 ±0.1
Data are shown as fold change ±standard error. DIO n =12–14; chow n =5–7.*Indicates p <0.05 vs. control; **Indicates p <0.01 vs. control, #Indicates different in SF between DIO
and chow.
signaling (Peterson et al., 2008). However, hyperphysiological
levels of leptin also stimulate the proliferation and activation
of macrophages, which may be a mechanism by which leptin
concentration influences tissue damage (Santos-Alvarez
et al., 1999). Leptin may also positively upregulate myostatin
(Rodríguez et al., 2015), a member of the TGF-βsuperfamily that
negatively regulates muscle mass and growth, and a molecule
which is up-regulated in muscle from individuals with metabolic
disturbance (Hittel et al., 2009). Upregulation of follistatin has
been an effective treatment for muscle degenerative diseases by
increasing muscle growth due to its ability to inhibit myostatin,
a negative regulator of muscle mass. Follistatin also alleviates
synovitis and mitigates OA-like changes from inflammatory
arthritis in mice (Yamada et al., 2014). As muscle has a role
in OA pathogenesis, protecting both muscles and joints with
follistatin represents an attractive therapeutic opportunity for
MetS-induced musculoskeletal damage.
Leptin also may be involved in mediating the pathogenesis of
osteoarthritis in humans (Fowler-Brown et al., 2014) and other
animals (Griffin et al., 2009, 2010, 2012; Collins et al., 2015a,b,
2016b). Leptin is found in synovial fluid of humans (Lübbeke
et al., 2013) and other animals (Collins et al., 2015a,b, 2016b).
Unpublished mRNA data (Table 2); from our laboratory indicate
increased mRNA expression levels for leptin in the fat pad and
synovium of rats with DIO compared to those on a chow diet,
after a 12-week obesity induction period.
Additionally, leptin may be involved in mediating the
pathogenesis of osteoarthritis in humans (Fowler-Brown et al.,
2014) and other animals (Griffin et al., 2009, 2010, 2012; Collins
et al., 2015a,b, 2016b). Leptin is found in synovial fluid of humans
(Lübbeke et al., 2013) and other animals (Collins et al., 2015a,b,
2016b). Increased mRNA levels for leptin were accompanied
by increased leptin in the serum and synovial fluid (Collins
et al., 2016b). After 28-weeks of DIO, the fat pad and synovium
demonstrated disparate up-regulation of IL-1β, although IL-1β
was detected in the synovial fluid of these animals (Collins
et al., 2015a). These findings suggest that the fat pad and
synovium contribute to increased pro-inflammatory synovial
fluid profiles (Collins et al., 2016b). However, cartilage explants
are not substantially damaged when exposed to physiological
levels of leptin (Griffin et al., 2010), despite reports of associations
between leptin and MMPs (Koskinen et al., 2011), calling into
question the direct involvement of leptin in eliciting cartilage
damage.
In the context of bone, leptin influences the formtion and
resorption of mineralized tissue by increasing the activity of
osteoclasts through RANKL (Ducy et al., 2000). However, there
are also reports that leptin supports bone growth and bone
MSC differentiation into osteoblasts (Thomas et al., 1999), so
the precise mechanism for leptin’s effects on bone is unclear,
but likely is dependent on exposure and dose (Kawai et al.,
2009). Low-level systemic inflammation and leptin can negatively
influence tendon structural integrity (Abate, 2014; Abate et al.,
2016), can result in accelerated heterotopic ossification in tendon
tissues (Jiang et al., 2017) and may be associated with increases
in tendon ruptures (Ji et al., 2010). Taken together, increases
in systemic leptin—or mediators downstream of leptin—appear
to have deleterious effects on all major musculoskeletal tissues.
These data support the notion that catabolic activity as a result
of increased leptin is an important pathway to clarify in the
context of global musculoskeletal integrity (Griffin et al., 2009).
More details regarding the interface among leptin signaling,
inflammation, metabolism, and musculoskeletal disorders are
detailed elsewhere (Abella et al., 2017b).
Resistin is an adipokine involved in insulin resistance,
inflammation, and energy homeostasis. Serum resistin levels are
reported to be derived from visceral adipose tissue (Milan et al.,
2002). There is conflicting evidence as to whether resistin is
associated with bone mineral density (Mohiti-Ardekani et al.,
2014). Within the joint, synovial fluid levels of resistin are
associated with inflammatory and catabolic molecules in the
joints of human osteoarthritis patients (Koskinen et al., 2014).
However, resistin and visfatin, demonstrated positive predictive
relations with recovery from upper extremity soft tissue disorders
such as tendinopathy, and are thought to be related to anti-
inflammatory response mechanisms (Rechardt et al., 2014).
Adiponectin, another adipokine, is derived from visceral fat,
and is thought to serve a protective role on cardiovascular
health and glucose homeostasis (Milan et al., 2002). As body fat
decreases, adiponectin levels generally increase, and adiponectin
may modulate adipose tissue regulation via NF-κB (Ajuwon
and Spurlock, 2005). Specifically, adiponectin treatment in
obese mice increases bacterial clearance and hematopoietic
progenitor proliferation in bone marrow (Masamoto et al.,
2016). Adiponectin was shown to be significantly correlated
with bone mineral density in a group of osteoporotic and
healthy patients (Mohiti-Ardekani et al., 2014). Adiponectin has
also been proposed as a systemic biomarker of OA. Plasma
adiponectin was significantly higher in a population of OA
patients and was also higher in women with erosive hand OA
compared to patients with non-erosive OA (Filková et al., 2009).
In a separate cohort of hand OA patients, the individuals with
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Collins et al. Obesity, MetS, and Musculoskeletal Disease
the highest levels of adiponectin demonstrated a decreased risk
for hand OA progression (Yusuf et al., 2011). However, the
study populations were not the same in these two reports (i.e.,
total numbers, males and females vs. females alone, and use
of European populations potentially differing genetically) and
therefore, additional research needs to be performed to better
evaluate this relationship. Additionally, in a study evaluating
76 males in Thailand with knee OA revealed that levels of
adiponectin in synovial fluid correlated with disease severity
(Honsawek and Chayanupatkul, 2010). In muscle, adiponectin
has been shown to increase fatty acid oxidation and glucose
uptake, and to attenuate local inflammation (Nigro et al.,
2015). Adiponectin has been proposed as a treatment for
diabetic tendinopathy (Rothan et al., 2013), suggesting it may
be protective and have favorable anti-inflammatory effects across
MSK tissues.
Progranulin is a more recently identified adipokine that
may also have anti-inflammatory characteristics. mRNA levels
for progranulin are increased in cartilage, synovium, and
infrapatellar fat pads from OA patients, and mRNA levels
are increased in response to pro-inflammatory stimulation
(Abella et al., 2016). Specifically, progranulin has been shown
to counteract pro-inflammatory molecule expression (i.e., NOS,
MMP-13) induced by IL-1βand the LPS-TLR-4 axis (Abella
et al., 2016). Attstrin, a progranulin-derived peptide, is a
promising therapeutic candidate for osteoarthritis (Abella et al.,
2017a) given that progranulin can counteract IL-1 driven
inflammation through TNFR1 in human chondrocytes, and
intraarticular injection of progranulin-derived attstrin prevented
OA-progression in a surgical model of murine OA (Xia et al.,
2015).
Obesity and Involvement of Cells of the
Inflammatory System
Macrophages
Generally speaking, macrophages are dichotomized into M1
(pro-inflammatory) and M2 (anti-inflammatory) phenotypes
based on their activity during tissue repair processes (Novak
and Koh, 2013). However, it is understood that this dichotomy
represents an oversimplification based on in vitro data which
may not accurately represent in vivo states (Martinez and
Gordon, 2014). Macrophages are described to demonstrate a high
degree of functional plasticity and their phenotypes can change
based on environmental stimuli (Stout and Suttles, 2004). It is
likely useful to consider macrophage activation as a spectrum
rather than a binary categorization (Mosser and Edwards, 2008),
but for the purposes of this review, and concordant with the
current musculoskeletal literature, macrophage activity and these
relations are generalized using the M1/M2 paradigm.
Macrophages are derived from monocyte precursor cells.
Tissues have resident macrophages, which are responsible for
general tissue maintenance. These macrophages are described
as alternatively activated, or M2 macrophages, and are induced
by TGF-β, IL-4, and IL-13 (Gordon and Martinez, 2010).
M1 macrophages (classically activated macrophages) are key
phagocytes within tissues, and are induced through IFN-γ
activation and LPS-induced TLR signaling or from detection
of pathogen-associated molecular patterns (Lampiasi et al.,
2016). With obesity, stress, loading, or tissue and niche specific
control mechanisms, M2-type macrophages may experience a
phenotypic shift. This shift may be influenced by exposure to
certain cytokines through their general signaling mechanisms or
in the presence of other conditions, including IL-6 (Braune et al.,
2017) or TNF-α(Wu et al., 2015). AGEs can also play a role in
M2 to M1 polarization (Jin et al., 2015) (Figure 5). Typically,
an imbalance in the ratio of M1:M2 macrophages is considered
maladaptive, creating an imbalance toward tissue degradation
and an absence of adequate repair. MAPK is a key pathway in
macrophage-mediated inflammatory responses and may play a
significant role in diseases mediated by macrophages (Yang et al.,
2014).
Within 24 hours following muscle damage, thousands of
macrophages have infiltrated the damaged tissue (Tidball,
2005; Grounds, 2011). Pro-inflammatory M1-macrophages first
perform cell lysis, removing necrotic muscle tissue debris
(Laumonier and Menetrey, 2016). Anti-inflammatory M2-
macrophages infiltrate the damaged site once M1-macrophages
have removed necrotic debris (∼48 hours following injury),
helping resolve the inflammatory response while promoting
myogenesis (Akhmedov and Berdeaux, 2013). Through the
secretion of a number of growth factors, macrophages promote
angiogenesis (FGF, TGF-β), synthesis of ECM proteins (TGF-
β), and activation of satellite cells, all promoting myogenesis
(Grounds, 2011).
It is possible that an increased presence of M1 macrophage
cells in a tissue is an early sign of disrupted tissue homeostasis
and repair. With diet-induced obesity, M1-type macrophages are
present in the quadriceps muscle of mice (Fink et al., 2014),
rats (Collins et al., 2016c), and humans (Fink et al., 2014;
Khan et al., 2015). In bone, osteoclasts are considered M1-type
macrophages. With a high-fat diet, bone loss is accelerated in
young mice due to increased osteoclastogenesis (Shu et al., 2015),
and as noted, pro-inflammatory cytokines increase osteoclast
activity in humans with obesity through activation of the NF-
κB/RANKL pathway (Cao, 2011). In the context of the joint
as an organ (Frank et al., 2004), the infrapatellar fat pad does
not demonstrate inflammation or M1 polarization prior to knee
OA in mice (Barboza et al., 2017). Synovial membrane samples
from OA patients reveal markers for M1 macrophages (IL-1α,
IL-1β, and TNF-α) and decreased levels of the M2 marker IL-
1RA (Smith et al., 1997). As such, it is challenging to determine
if levels of M1/M2 macrophages are a cause or consequence
of disease. In rabbits, intra-articular injections of the pro-
inflammatory mediators IL-1 and TNF-αstimulate M1 activation
and degrade cartilage, suggesting macrophage polarization may
occur in synovial cells (Pettipher et al., 1986; Henderson and
Pettipher, 1989). Conditional macrophage depletion in obese
mice with a knee injury does not mitigate OA severity (Wu
et al., 2017b). Moreover, in mice where macrophages were
depleted, there was an increase in neutrophils and CD3+T
cells compared to control animals (Wu et al., 2017b). These
data suggest that a potential redundancy may exist between
macrophages and other inflammatory cells. Macrophages may
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Collins et al. Obesity, MetS, and Musculoskeletal Disease
modulate inflammatory homeostasis within the joint OA and
obesity, and that a basal level of macrophages are likely needed to
maintain joint health (Wu et al., 2017b). While this study is not
conclusive, it demonstrates that the relations among macrophage
polarization and presence in obesity and OA are complex. It is
important to note that what constitutes a healthy or maladaptive
balance in macrophage phenotype in one tissue or disease may
differ from another tissue or disease process. As such, these
findings are likely context- and tissue-dependent. More studies
are needed to better understand whether synovial macrophage
polarization, mitigation/modulation, or ablation is a promising
therapeutic target in OA pathogenesis (Sun et al., 2016).
SPECIFIC CELL INVOLVEMENT IN
METABOLIC OVERLOAD WITH OBESITY
Many cells (e.g., adipocytes, hepatocytes, and myocytes)
contribute to the conversion of food into chemical energy
and can be placed under significant metabolic stress when
exposed to a typical western-style diet. Significant increases in
the postprandial flux of metabolic substrates results in drastic
nutrient spikes characterized by elevated glucose, free fatty
acid (FFA), and triglyceride (TG) levels (Weiss et al., 2013).
Chronic nutrient overload places metabolic pathways under
significant stress, overwhelming subcutaneous adipose depots,
leading to adipocyte mitochondrial dysfunction and impaired
insulin sensitivity (Miranda et al., 2005). Normally, insulin
inhibits lipolysis and promotes glucose transport. However,
during chronic metabolic overload, mitochondrial dysfunction
can disrupt adipocyte insulin signaling pathways, leading to
impaired glucose transport into adipocytes and the inability to
suppress cell lipolysis, further increasing blood glucose and free
fatty acid (FFA) levels in circulation (Miranda et al., 2005). As
a result of increased circulating blood glucose and FFA levels,
hepatocytes and myocytes are placed under great metabolic
stress.
Mitochondrial Dysfunction and Adipose
Adaptations with Metabolic Challenge
With the onset of metabolic challenge, the imbalance of redox
states and mitochondrial dysfunction may be instrumental to the
development of insulin resistance and MetS (Long et al., 2015).
With nutrient overload, mitochondrial dysfunction in adipose
tissue will give rise to an increase in inflammatory mediators
(adipokines) resulting in tissue remodeling, and potentially
cell death (Trayhurn, 2005; Vernochet et al., 2014). Adipokine
dysregulation can result in the fibrosis, or inadequate healing