MAP kinase phosphatase-1 - a new player at the nexus between sarcopenia and metabolic disease
Abstract
Sarcopenia, which is defined by the loss of skeletal muscle mass, predisposes skeletal muscle to metabolic dysfunction which can precipitate metabolic disease. Similarly, overnutrition, which is a major health problem in modern society, also causes metabolic dysfunction in skeletal muscle and predisposition to metabolic disease. It is now the prevailing view that both aging and overnutrition negatively impact skeletal muscle metabolic homeostasis through deleterious effects on the mitochondria. Accordingly, interplay between the molecular pathways implicated in aging and overnutrition that induce mitochondrial dysfunction are apparent. Recent work from our laboratory has uncovered the stress-responsive mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) as a new player in the regulation of metabolic homeostasis in skeletal muscle and mitochondrial dysfunction caused by overnutrition. These observations raise the intriguing possibility that MKP-1 may function as a common target in the convergence between sarcopenia and overnutrition in a pathophysiological pathway that leads to a loss of skeletal muscle mitochondrial function. With the increasing aging population it will become more important to understand how MKP-1, and possibly other phosphatases, operate at the nexus between sarcopenia and metabolic disease.
Skeletal muscle is a major contributor to
resting levels of energy expenditure [1], and reduced
skeletal muscle function contributes to age-induced obesity and diabetes.
Disruption of skeletal muscle function may also contribute to insulin
resistance and diabetes caused by overnutrition and obesity [2]. There is
increasing evidence that similar molecular pathways are at work in promoting
age-related and obesity-related muscle dysfunction. These pathways seem to
converge at the level of mitochondrial dysfunction.
The overall metabolic capacity of
skeletal muscle is determined by the myofiber type of the particular muscle.
Though less abundant, oxidative/slow twitch (MHC type I, IIa) muscle fibers are
important for overall metabolic wellness. However, the most abundant myofibers
are glycolytic or fast twitch (MHC type IIx/IIB) muscle fibers which mainly
utilize glycolysis to metabolize glucose. Oxidative myofibers have increased
mitochondria, more blood flow, and are resistant to fatigue. In contrast,
glycolytic fibers have the least amount of mitochondria, and fatigue easily [2,3].
Skeletal
muscle fiber type establishment is regulated by changes in calcium flux,
nervous system inputs, and transcriptional events and is a dynamic process.
Endurance exercise increases oxidative capacity of skeletal muscle, and to this
end, human studies have shown that endurance athletes have increased amounts of
MHC type I [2]. During
periods of inactivity, fibers switch from oxidative to more glycolytic types [4].
Furthermore, an increased proportion of glycolytic fibers have been
demonstrated in the elderly population as well as diet-induced obese
populations [2,3]. However,
it is not well understood whether these changes in myofiber content are causal
to age- and overnutrition-induced obesity and insulin resistance, or whether
they are merely consequences of these events.
One
hallmark of the aging process is the progressive atrophy of skeletal muscle
leading to weakness and frailness, a condition termed sarcopenia, which is also
associated with increased obesity in elderly [5]. It is
thought that the occurrence of sarcopenia in the elderly is
related to a switch in myofiber composition, a loss of muscle stem cell number,
and decreased mitochondrial function [6,7]. To this
end, mitochondrial number and function decreases with age in human subjects [8,9]. Numerous
hypotheses have surfaced as to why mitochondrial function decreases with age. These
hypotheses include increased reactive oxygen species (ROS) production, chronic
inflammation and/or mitochondrial DNA damage [8,10-14]. One
may draw many comparisons between the decline in skeletal muscle function that
occurs with aging and mitochondrial dysfunction in the skeletal muscle of
individuals that consume high levels of calories. Recent work has demonstrated
that mitochondrial damage occurs in obesity due to enhanced ROS and chronic
inflammation caused by increased fatty acid load [15-17]. These
data suggest that modulation of fatty acid-driven signaling pathways,
inflammatory pathways, or ROS may prevent mitochondrial damage and thus,
enhance skeletal muscle oxidative capacity, therefore improving overall metabolic
performance.
Figure 1. Potential relationship between aging, overnutrition and MKP-1-mediated regulation of skeletal muscle mitochondrial function.
Molecular
targets controlling skeletal muscle function and their impact on aging
Calcineurin/NFAT - Through transgenic and knockout mouse models,
calcineurin, a calcium-activated phosphatase (also known as protein phosphatase
2B), has been shown to be necessary to drive the slow twitch MHC phenotype [18-20].
Calcineurin does this by controlling the phosphorylation status of a
transcription factor called nuclear factor of activated T-cells (NFAT), which
is activated upon dephosphorylation. Active NFAT enhances transcription of
genes that promote a slow-twitch myofiber phenotype [18,21].
Interestingly, calcineurin has been demonstrated to increase in activity with
age in a ROS-dependent manner, and correlates with age-induced muscle
dysfunction [22].
MAP
Kinases - The MAPKs consist of growth factor-regulated
extracellular signal related kinases 1 and 2 (ERK1/2), and the stress-activated
MAPKs, c-jun NH2-terminal kinase (JNK) and p38 MAPK [23]. MAPKs are
activated by phosphorylation on regulatory tyrosine and threonine residues by
upstream MAP kinase kinases (MKKs), and are inactivated by dephosphorylation on
these same regulatory residues by MAPK phosphatases (MKPs) [23,24].
Although it is appreciated that MAPKs play an essential role in myogenesis,
relatively little is known about the involvement of the MAPKs in fiber type
establishment. A role for ERK1/2 has been demonstrated in slow-fiber type
expression, as constitutively active Ras increases MHC type I expression [25]. There is
also evidence that p38 MAPK is able to drive MHC type IIx (intermediate) gene
expression in myoblasts [26].
Increased
MAPK activity after exercise has been shown to be important for
exercise-mediated gene expression, which may contribute to the role of exercise
ameliorating the effects of aging in skeletal muscle [27]. Though the
contribution of MAPKs in aging has not been convincingly addressed in
vertebrates, some studies in drosophila as well as c. elegans
have demonstrated a role for MAPKs for enhancement of lifespan. Whereas the
role of p38 MAPK in promotion of lifespan is controversial [28,29], JNK
activity enhances lifespan by antagonizing insulin signaling [30,31].
Additionally, decreased ERK1/2 activity throughout aging is known to promote
senescence [32]. These data
suggest the possibility that decreased MAPK activity during aging may have
deleterious effects on metabolic health and lifespan.
PGC-1α - The transcriptional co-activator peroxisome
proliferator-activated receptor gamma co-activator 1-α (PGC-1α)
drives mitochondrial biogenesis and function and additionally is important in
the cellular defense against reactive oxygen species [33,34].
Specifically, in skeletal muscle, the expression of PGC-1α drives not only
mitochondrial biogenesis and oxidative myofiber establishment but also
vascularization [35-37]. It has
been found that a high fat diet or fatty acid treatment causes a reduction in
the expression of PGC-1α and other mitochondrial genes in skeletal muscle [38-40], which
may be a mechanism through which excess caloric intake impairs skeletal muscle
function.
Recent
work has also demonstrated that transgenic overexpression of PGC-1α in
skeletal muscle improves sarcopenia and obesity associated with aging in mice [41]. This
implies that pharmacological control of stability or expression of PGC-1α
may be a therapeutic option for the elderly to ameliorate metabolic
dysfunction. Pharmacological modulation of protein stability remains somewhat
challenging and so alternative strategies targeting regulators of PGC-1α
function are likely to meet with more success. Stability of PGC-1α has
been shown to be driven by both acetylation as well as phosphorylation [42,43].
Stability and activity of PGC-1α is enhanced by phosphorylation by p38
MAPK [43] which again raises the interesting issue of the role of the MAPKs in
both sarcopenia and in responses to overnutrition.
MAP
Kinase Phosphatases - MKPs are dual-specificity phosphatases that constitute
a sub-family of the protein tyrosine phosphatase (PTP) superfamily [44]. MKPs are
classified into three subgroups based on subcellular localization, tissue
distribution and substrate preference [44,45]. MKP-1
is the founding member of this family of enzymes and is a nuclear-localized,
immediate-early gene that is responsive to numerous stimuli including ROS,
cytokines, growth factors, and fatty acids [15,46]. MKP-1
expression is confined to the nucleus and therefore is restricted to the
dephosphorylation of the nuclear pool of active MAPKs [47]. Though
MKP-1 has the ability to dephosphorylate all three MAPKs, it displays substrate
preference to the stress-responsive MAPKs, p38 MAPK and JNK [48,49].
As
discussed, enhanced ROS, cytokines and fatty acids can induce the expression of
MKP-1 [15,46]. Therefore, it is conceivable that increased MKP‑1
expression in response to stresses such as these might play a role in the
demise of skeletal muscle mitochondrial function. Indeed, we had provided the
first insight into a potential connection between mitochondrial function and
MKP-1 [47]. We showed
that in mice lacking MKP-1 mitochondrial oxidative phosphorylation was enhanced
in the oxidative portions of skeletal muscle [47]. Consistent
with this MKP-1-deficient mice exhibit enhanced levels of energy expenditure
and were resistant to diet-induced obesity [47]. These
results provide genetic evidence that MKP-1 is connected, through modulation of
the MAPKs, to mitochondrial function in skeletal muscle as well as whole body
energetics. It is tempting to speculate that age- and diet-induced stresses that
promote deleterious mitochondrial function could be attributed to the
convergence, at least in part, to the overexpression of MKP-1 in skeletal
muscle.
More
recently we have been able to provide mechanistic insight in to the pathway
linking MKP-1 to mitochondrial function. We have found that MKP-1 is a key
regulator of the master controller of mitochondrial biogenesis, PGC-1α [15]. When mice
are fed a high-fat diet, the expression levels of MKP-1 in skeletal muscle
increase which results in a reduction in PGC-1α levels. In contrast,
PGC-1α levels are maintained in mice lacking MKP-1 [15]. Consistent
with the notion that PGC-1α promotes oxidative myofiber composition
MKP-1-deficient mice are refractory to the switch from oxidative to glycolytic
myofibers seen in wild type mice fed a high fat diet and remain lean. These
observations support the idea that MKP-1 plays an important role in maintaining
skeletal muscle health. Mechanistically, MKP-1 appears to control a pool of
nuclear p38 MAPK activity that is responsible for phosphorylating PGC-1α
on residues that promote its stability. Therefore, increased MKP-1 expression
levels result in a reduction of p38 MAPK-mediated PGC-1α phosphorylation
and ultimately, stability. Collectively, these observations raise the
possibility that impairment in mitochondrial function might arise through
disturbing the dynamic homeostatic balance between MKP-1 and p38 MAPK activity
in the nucleus. The precise contribution of MKP-1, as well as other MKPs which
have the capacity to dephosphorylate p38 MAPK in the nucleus, to mitochondrial
dysfunction in either aging or overnutrition still remains to be fully
realized. Nevertheless, these recent insights provide a platform from which
these questions can be addressed.
Phosphatases
in aging
The role of PTPs in the aging process is
largely unknown. On a broad scale, enhanced phosphatase activity has been
associated with cellular senescence [32,50]. It is
also recognized that ROS, which inhibit PTPs by modification of the catalytic
cysteine [51], are
increased during the aging process. The enhanced levels of ROS during aging are
likely due to the increased production of pro-inflammatory cytokines [13,52], and
reduced antioxidant defenses [13]. However,
even though ROS inhibit phosphatase activity, enhanced ROS levels are also
known to drive cellular senescence [53], suggesting
a potential role for PTPs both in promoting as well as inhibiting senescence.
ROS also elicits a cellular stress response, which may induce stress-responsive
phosphatases, such as the MKPs, to serve as negative regulators of excessive
MAPK activity [54,55]. More
studies are warranted to determine what role enhanced ROS in a whole organism
has on modulation of PTP activity during aging.
In
support of the data that similar mechanisms are at work in overnutrition as
well as age-induced metabolic dysfunction, our laboratory has demonstrated that
mice lacking MKP-1 are resistant to age-induced obesity, in the absence of a
high fat diet [47]. Moreover,
MKP-1 expression in skeletal muscle of aged human patients has been shown to be
enhanced [56]. Though the
mechanisms behind the resistance to age-induced obesity in mice lacking MKP-1
have not yet been defined, one may hypothesize that similar mechanisms also
apply as those in a high fat diet scenario. For example, increases in cellular
insults such as ROS and intramyocellular lipids, which increase during aging [57,58], may
trigger increased MKP-1expression, thus negatively regulating p38 MAPK
activity, and therefore, PGC-1α stability. Consistent with this notion, as
previously discussed, PGC-1α expression is sufficient to relieve rodents
of age-related sarcopenia [41]. It is
unclear however, how ROS may promote increased levels of MKP-1 expression
without affecting catalytic activity. Nevertheless, modulation of p38 MAPK
activity by MKP-1 may be important in the progression of age-related sarcopenia
and obesity.
Treatments
for sarcopenia
Caloric
Restriction - Calorie restriction is perhaps the most well
recognized anti-aging therapy, and exerts this effect in multiple ways [13]. Calorie
restriction has an anti-inflammatory effect and is important for decreasing
oxidant production during aging [13]. In
addition, calorie restriction is associated with decreased MAPK activity [13].
Provocatively, calorie restriction may serve to prevent the reported increase
in MKP-1 levels during aging. Increased MKP-1 levels during aging would reduce
PGC‑1α levels thereby removing the protective effects of stressors
on skeletal muscle. Calorie restriction also activates the deacetylase SIRT1,
which is a positive regulator of longevity in c. elegans[59]. To this
end, SIRT1 also promotes PGC-1α activity by deacetylation [42], thus
demonstrating a role for calorie restriction in promotion of PGC-1α
activity. Interestingly, acetylation is also known to enhance the phosphatase
function of MKP-1 [60]. One
hypothesis may be that SIRT1 deacetylates, and therefore decreases activity of
MKP‑1, leading to increased PGC-1α function, thus, preventing
myofiber dysfunction.
Exercise - Moderate
exercise retards the aging process, and additionally induces an oxidative
muscle phenotype [13]. Several
hypotheses have arisen regarding the role of exercise in aging. Leading
hypotheses include the fact that a moderate exercise regimen reduces
pro-inflammatory cytokine production and chronic inflammation. The reduced
level of inflammation leads to a decrease in ROS production, which lessens DNA
damage [13]. Other groups
have demonstrated that resistance training enhances myofiber size and
contractility, thus preventing age-mediated myofiber loss [61,62].
Importantly, exercise has been shown to induce MAPK activity in skeletal
muscle, which is important for exercise-mediated gene expression [27]. In
particular, p38 MAPK is known to drive PGC-1α transcription as well as
stability in skeletal muscle [43,63]. In
animals lacking MKP-1 expression, it would be important to determine if the
enhanced MAPK activity in skeletal muscle promotes similar gene expression
events as exercise. If this is the case, mice lacking MKP-1 may exhibit
characteristics similar to that of the molecular effects of exercise.
Perspective
It
is now well accepted that aging is an underlying predisposition to metabolic
disease. Not surprisingly, the pathways that succumb to the deleterious effects
of aging often seem to be those that also control metabolism. Protein tyrosine
phosphatases have not featured as prominent targets for convergence for these
two pathophysiological processes up until now. MKP-1 appears to exhibit
characteristics that afford it the ability to respond to age-related stresses
such as increased ROS and free fatty acids in skeletal muscle. If in fact MKP-1
plays a major role in the convergence in skeletal muscle between aging and
susceptibility to metabolic disease, how this phosphatase is regulated by such
external factors needs to be addressed in significantly more depth. One
intriguing, and as yet to be tested idea, is whether MKP-1 is more deeply
intertwined with other pathways that control longevity such as the SIRTs. As
such, it will be interesting to determine whether there is a longevity
phenotype in mice lacking MKP-1. Clearly, these ideas set the stage for further
work to be conducted on age- and nutrition-related consequences, not only on
MKP-1, but also other protein tyrosine phosphatases in skeletal muscle.
Acknowledgments
A.M.B. is supported by NIH grants AR46504
and DK57751.
R.J.R.F was supported by T32 DK07356.
Conflicts of Interest
The authors of this manuscript have no
conflict of interest to declare.
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