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Endurance Exercise Mimetics in Skeletal Muscle

Matsakas, Antonios; Narkar, Vihang A.

Current Sports Medicine Reports: July-August 2010 - Volume 9 - Issue 4 - p 227-232
doi: 10.1249/JSR.0b013e3181e93938
Nutrition & Ergogenic Aids: Section Articles
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Regular exercise promotes favorable structural and metabolic adaptations, especially in the skeletal muscle, to boost endurance and cardiovascular health. These changes are driven by a network of incompletely understood molecular pathways that trigger transcriptional remodeling of the skeletal muscle. In this article, we describe recent advances in the understanding of the key components of this circuitry [namely peroxisome proliferator activator receptor delta (PPARδ), adenosine monophosphate (AMP)-activated protein kinase (AMPK), silent information regulator two protein 1 (SIRT1), and peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α)] that govern aerobic transformation of the skeletal muscles. We also discuss recent discoveries that raise the possibility of synthetically mimicking exercise with pathway-specific drugs to improve aerobic capacity and, in turn, health.

Center for Diabetes and Obesity Research, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX

Address for correspondence: Vihang A. Narkar, Ph.D., Center for Diabetes and Obesity Research, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, 1825 Pressler St, IMM/SRB 430F, Houston, TX 77030 (E-mail: vihang.a.narkar@uth.tmc.edu).

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INTRODUCTION

Endurance exercise long has been known to be beneficial in the management of metabolic diseases, as well as related cardiovascular complications. While the effects of exercise are megaphysiologic, remodeling of the skeletal muscle is crucial for increasing endurance as well as metabolic efficiency. Skeletal muscle is a highly heterogeneous and plastic tissue composed of oxidative slow-twitch (type I), oxidative/glycolytic fast-twitch (type IIa), oxidative fast-twitch (type IIx), and glycolytic fast-twitch (type IIb) myofibers that vary in metabolic and contractile properties (14). Slow-twitch fibers express high levels of fat-oxidizing enzymes, mitochondria, and slow contractile proteins. On the other hand, fast-twitch myofibers preferentially and anaerobically metabolize glucose by virtue of limited mitochondrial content and express the fast contractile proteins. Both its metabolic and contractile properties impart high-fatigue resistance to oxidative and slow-twitch muscle. Endurance exercise triggers transdifferentiation of skeletal muscles towards oxidative slow-twitch phenotype by increasing slow-twitch contractile machinery, mitochondrial biogenesis, and fatty acid oxidation that ultimately leads to an increase in aerobic capacity (23). Such remodeling not only improves exercise performance, but also retards diseases such as obesity and type 2 diabetes that commonly are associated with loss of aerobic muscles. However, endurance exercise as a therapy for obesity and even cardiovascular complications often is impractical because of physical limitations. Therefore, the discovery of drugs that mimic endurance exercise will have tremendous therapeutic implications in these diseases.

Exercise triggers aerobic adaptations and improves performance by activating a signaling and transcriptional circuitry that induces genetic changes, especially in the skeletal muscles (5). Because of the complexity of this circuitry, endurance generally is believed to be resilient to replication by pathway-specific drugs. This article will focus on recent advances in the discovery of transcriptional regulators that have endurance exercise-like effects in skeletal muscle, specifically emphasizing signaling factors [namely peroxisome proliferator-activated receptor delta (PPARδ), AMP-activated protein kinase (AMPK), silent information regulator two protein 1 (SIRT1), and peroxisome proliferator activated receptor γ coactivator-1alpha (PGC-1α)] with known pharmacological activators.

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PPARδ

PPARδ is a member of the nuclear receptor super-family of transcriptional regulators. Nuclear receptors are hormone-activated transcription factors known for their prominent role in development, differentiation, and energy homeostasis (36). The super-family consists of steroid receptors activated by hormones such as retinoic acid, thyroid (TR) hormone, and glucocorticoids (GR), as well as a large subclass of orphan receptors whose endogenous hormones remain to be identified. A large number of nuclear receptors, including steroids receptors [GR, androgen (AR), and TR receptors] and several orphan receptors [e.g., peroxisome proliferator-activated receptor (PPAR) and estrogen receptor-related receptors (ERR)], are expressed in the skeletal muscle (6). As the role of multiple receptors in skeletal muscle biology is beginning to be deciphered (48), PPARδ has emerged as a key regulator that mimics exercise in the context of metabolic effects, fiber type remodeling, and running endurance.

PPARδ is expressed abundantly in several metabolically active tissues, including skeletal muscle. Within the skeletal muscles, PPARδ predominantly is expressed in oxidative slow-twitch compared with glycolytic fast-twitch muscle fibers (55). PPARδ expression in the skeletal muscle is induced further by endurance-type exercise known to trigger adaptive increase in oxidative and/or slow-twitch phenotype (34).

Numerous in vitro, ex vivo, and in vivo studies have shed light on the effects of PPARδ in skeletal muscle. The preliminary discoveries were made independently by various groups that found that forced overexpression of PPARδ in cultured muscle cells increased fatty acid uptake and oxidation via upregulation of oxidative genes (12,24). More physiological evidence for the regulatory effects of PPARδ on metabolism and fiber type and in turn energy homeostasis and endurance has been gathered from mouse genetic engineering studies. Wang et al. found that overexpression of a constitutively active PPARδ (VP16-PPARδ) induces a red transformation of the skeletal muscle beds, increasing mitochondrial biogenesis and the proportion of type I oxidative myofibers (55). These changes were linked to programming of muscle genome by PPARδ to increase gene expression linked to fat oxidation (e.g., CPT I, UCP3, PDK4), mitochondrial biogenesis/respiration (e.g., COX II, COX IV, cyt c), and slow-twitch fibers (PGC-1α, myoglobin, troponin I slow) (55). More importantly, the authors found that this muscle-specific PPARδ activation was sufficient to induce exercise-like effects, namely increased running endurance and protection against diet-induced obesity and type 2 diabetes. Interestingly, overexpression of wild-type PPARδ in skeletal muscle has similar remodeling effects as the constitutively active receptor (34). This particular observation points towards the availability of endogenous ligand or coregulator that sustainably can activate the halo-receptor, as well as raises the notion that regulating PPARδ levels might be sufficient to trigger a fiber type remodeling program. This argument is supported by the findings that muscle-specific knockout of PPARδ results in an age-dependent loss of oxidative muscle fibers, running endurance, and insulin sensitivity (45). Collectively, these reports provide a compelling argument that PPARδ is a master transcriptional regulator of oxidative metabolism and slow-twitch phenotype.

Several potent and selective PPARδ agonists such as GW1516 have been identified, which greatly has facilitated the pharmacological study of this receptor (42). We and others have used PPARδ agonists to determine whether synthetic activation of the receptor has exercise-like effects similar to those observed in genetic mouse models. We found that treatment with GW1516 alone was insufficient to change fiber type or running endurance in adult C57Bl/6J mice (39). Genome-wide comparison in these studies revealed that GW1516 only partly mimicked the global effects of exercise on skeletal muscle gene expression, explaining the lack of drug effect on these parameters. Kleiner and colleagues found similar partial effects on gene expression and metabolism in cultured muscle cells (29). The inability of GW1516 to change skeletal muscle composition and endurance suggests that once fiber-type specification is complete in adults, any reprogramming by drugs targeting a "single transcriptional factor" is limited and can be attained only by an integrated stimuli such as exercise. On the other hand, a more robust transgenic activation of PPARδ occurs at birth in the transgenic mice, thus preprogramming the nascent myofibers to form, preferentially, oxidative slow-twitch fibers. Interestingly, pharmacological activation of PPARδ in exercise-trained mice increased oxidative slow-twitch muscles and running endurance. This effect was linked to a transcriptional synergism between PPARδ and exercise-activated signals such as serine/threonine kinase AMPK, leading to an increased muscle performance (39). These findings suggest that PPARδ agonists alone are partial exercise mimetics, whose full potential can be released by interacting with exercise-activated pathways. Nevertheless, PPARδ ligands may be beneficial in metabolic disorders even without exercise. Administration of GW1516 to high-fat-fed or genetically obese mice increased resting energy expenditure, retarded weight gain, and exerted insulin-sensitizing effects by remodeling dramatically the skeletal muscle to increase fatty acid oxidation and disposal (53,55). These findings further are corroborated by studies in cultured cells where PPARδ agonists were found to increase basal and insulin-stimulated glucose uptake (30,31) via activation of mitogen-activated protein kinase (MAPK) and AMPK signaling - providing further insight into the insulin-sensitizing mechanisms of the receptor. In a recent study, GW1516 also was shown to suppress atherosclerosis by regulating multiple proinflammatory pathways (3). Overall, these findings indicate that the PPARδ agonists may function as an exercise mimetic in the sense that they exert exercise-like benefits in pathophysiology.

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AMPK

AMPK is a fuel-sensing serine/threonine kinase that is activated under conditions of energetic demands, such as exercise, to restore energy balance (43). Specifically, AMPK is activated by an increase in the cellular AMP to adenosine 5' triphosphate (ATP) ratio, which occurs under fuel-depleting conditions. Upon activation, AMPK stimulates catabolic pathways and suppresses anabolic pathways in an effort to restore cellular ATP levels. AMPK is a heterotrimeric complex consisting of the catalytic α subunit and the regulatory β and γ subunits. Relative binding of AMP (or synthetic analog 5-Aminoimidazole-4-carboxyamide ribonucleoside [AICAR]) and ATP to the γ subunit leads to the allosteric activation of α subunit as well as its sensitization to multiple upstream kinases such as LKB1 (43). Alternatively, binding of AMP to the γ subunit is thought to repress the inhibition of the kinase by phosphatases (43). Each subunit exists in multiple isoforms (α1 and 2; β1 and 2; γ1, 2, and 3), and the combination of isoforms that form the kinase complex is tissue-dependent (43).

All isoforms of the AMPK subunits are expressed in the skeletal muscle. Of the catalytic subunits, α2 is more abundant than α1 (49). While the skeletal muscles express both β1 and 2 subunits, β2 is thought to be restricted to the fast-twitch myofibers (10). Likewise, all the γ isoforms are expressed, with γ3 being highly expressed in the fast-twitch muscles (35). AMPK is activated robustly by both acute and chronic exercise in skeletal muscle, and the isoforms recruited to the "active complex" are thought to depend on the intensity of the exercise (57).

Tissue-specific genetic studies in mice clearly underscore the role of AMPK in aerobic muscle physiology (15,16). Inactivation of AMPK specifically in the skeletal muscle by transgenic expression of dominant negative or inactive catalytic subunits leads to the loss of oxidative myofibers, decreased fat metabolism, and impaired mitochondrial biogenesis. These changes are responsible for decreased exercise performance, repressed insulin-stimulated muscle glucose uptake, and pathogenesis of insulin resistance in the transgenic mice (15,16). Conversely, transgenic expression of activating γ3 mutant specifically in skeletal muscle increases basal AMPK activity, leading to an increase in glycogen accumulation, oxidative metabolism, and resistance to diet-induced insulin resistance, as well as contraction-induced fatigue (4). Some of the physiologic effects of AMPK are linked to direct phosphorylation and activation of enzymes responsible for myocellular glucose uptake as well as fatty acid oxidation. Additionally, AMPK exerts long-term metabolic changes via transcriptional regulation of genes. Molecular evidence suggests that AMPK may mediate a part of its gene regulatory effects via coactivator PGC-1α and nuclear receptor PPARδ. AMPK directly phosphorylates PGC-1α to autoinduce the coactivator and additional aerobic genes in the skeletal muscle (27). We recently showed that AMPK boosts basal, ligand-mediated, and PGC-1α-dependent PPARδ transcriptional activity in inducing muscle endurance genes (39). Overall, these findings show that the genetic effects of AMPK involve a PGC-1α to PPARδ pathway.

AMPK can be activated pharmacologically by synthetic drugs such the AMP analog AICAR and antidiabetic drug metformin. Acute activation of AMPK by AICAR phosphorylates and inhibits acetyl CoA carboxylase, leading to an increase in fatty acid oxidation (37,56). On the other hand, chronic AICAR treatment promotes a fast- to slow-twitch fiber type transition and increases the expression of several metabolic enzymes linked to aerobic respiration (50,56). We found that chronic treatment of mice with AICAR activates AMPK, increases whole-body oxygen consumption, decreases adipose mass, and improves running endurance (39). These effects, in part, are mediated by PPARδ-dependent activation of fatty acid oxidation genes in the skeletal muscle. Additional studies suggest that the aforementioned aerobic adaptations could account for the antidiabetic effects of AMPK activation by AICAR (25). Furthermore, similar effects on skeletal muscle AMPK activation are reported for metformin (46). Therefore, pharmacological activation of AMPK mimics several of the endurance-enhancing aspects of exercise training. Identification of selective and potent pharmacological agents with high bioavailability that activate AMPK may serve as a potential approach to combat insulin resistance in type 2 diabetes.

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SIRT1

Sirtuins are an evolutionarily conserved class of deacetylases consisting of seven mammalian subtypes that are localized in multiple subcellular regions (20). The regulatory effects of sirtuins involve deacetylation of a variety of transcription factors, co-regulators, and enzymes. The enzymatic activity of sirtuins is in turn dependent on the cellular NAD+ to NADH ratio, posttranslational modifications, and protein-protein interactions. Sirtuins are involved in a diverse range of biological processes including differentiation, metabolism, and inflammation. Further, deregulation of sirtuins is implicated in diseases such as obesity, cancer, and aging (20). SIRT1 is the most extensively studied sirtuin, and accumulating evidence indicates that it is a critical regulator of energy homeostasis. SIRT1 regulates a variety of metabolic processes such as glucose homeostasis, insulin secretion, mitochondrial biogenesis, cell survival, and lipid metabolism and has biological effects in tissues such as fat, liver, pancreas, kidney, and skeletal muscle (20). SIRT1 expression primarily is induced in response to caloric restriction in both rodents and humans (20).

In skeletal muscle, SIRT1 is expressed preferentially in oxidative slow-twitch myofibrillar beds and is induced further by exercise (51). Specifically, acute exercise increases SIRT1 expression in the skeletal muscle within 2 h of an exercise bout (51). The effect of chronic exercise or muscle activity on the SIRT1 expression, on the other hand, remains to be elucidated fully. Both low- and high-intensity endurance training (4 wk) in rats, as well as chronic contractile activity (nerve stimulation), increase SIRT1 expression in skeletal muscle (25,51). However, chronic voluntary running (8 wk) fails to change muscle SIRT1 expression, suggesting an intensity and time dependency of SIRT1 activation in the skeletal muscle (9).

Pharmacological studies using natural (e.g., resveratrol) as well as synthetic activators have revealed the role of SIRT1 in skeletal muscle. Treatment of mice with high doses of resveratrol induces oxidative genes and mitochondrial biogenesis in skeletal muscle, leading to an increase in oxygen consumption, running endurance, and protection against obesity and type 2 diabetes (32). Although resveratrol has multiple biological targets, the aerobic effects of this drug are linked in part to SIRT1-dependent deacetylation and activation of PGC-1α (17,32). Recent studies confirm that potent and selective SIRT1 activators have similar effects as resveratrol via deacetylation of PGC-1α and additional transcriptional regulators such as FOXO1 and p53 (13,17,38). Notably, AMPK now has been found to activate SIRT1 in the skeletal muscle via the regulation of the NAD+ to NADH ratio, thus linking a critical energy sensor to a transcriptional aerobic regulator (8).

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PGC-1α

PGC-1α is one of the well-characterized transcriptional coactivators and was first identified as nuclear receptor PPARγ interacting protein in the brown adipocytes (22,41). Additional members of this family include PGC-1β and PGC-1-related protein, both of which have not been studied as extensively. PGC-1α exerts its coregulatory effect by binding to transcriptional factors and recruiting histone acetylases (e.g., CBP, p300, and SRC-1) as well as transcriptional initiating complexes (e.g., TRAP/DRIP) leading to gene activation. The transcriptional activity of PGC-1α, in turn, is regulated by changes in expression as well as posttranslational modifications such as phosphorylation, acetylation, and methylation (22).

The importance of PGC-1α in exercise training-induced skeletal muscle adaptation is underscored by the observation that both short-term and chronic physical exercise robustly increase PGC-1α mRNA expression in rodent muscles (2,26). In addition to changes in PGC-1α abundance, endurance exercise also triggers translocation of PGC-1α from the cytosol to the nucleus, presumably leading to an increase in its transcriptional effects (26).

In the skeletal muscle, PGC-1α preferentially is expressed in oxidative slow-twitch myofibers (33). Transgenic studies have shown that muscle-specific overexpression of PGC-1α triggers a fast- to slow-twitch transformation resulting in an increase in oxidative metabolism, mitochondrial biogenesis, and fatigue resistance (33). Curiously, and despite the increase in mitochondria, PGC-1α overexpression impairs insulin-stimulated glucose uptake resulting in insulin resistance (11). This paradoxical effect was linked to a greater increase in fat uptake by PGC-1α compared with oxidation, resulting in fat accumulation and PKC activation that interferes with insulin signaling. However, PGC-1α deficiency in skeletal muscle results in the loss of aerobic myofibers, exercise intolerance, and impaired glucose homeostasis (21). Taken together, the previously mentioned studies highlight the exercise-like effects of PGC-1α, providing a supportive background for exploring pharmacological targeting of PGC-1α. In this regard, Arany et al. recently identified microtubule inhibitors as inducers of PGC-1α, thus opening an avenue for chemically targeting this coactivator (1).

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CONCLUSION

Endurance exercise triggers cardiopulmonary, endocrine, vascular, and neuromuscular adaptations that collectively increase aerobic capacity and athletic performance (28). Nevertheless, skeletal muscle is the largest physiological system (40% of the body mass) recruited and remodeled by exercise. The singular importance of skeletal muscle is evident in the observation that transgenic expression of exercise-activated factor(s) such as PPARδ and PGC-1α (specifically in skeletal muscle) is sufficient to "reverse engineer" an athletic muscle and improve endurance without having to exercise. Therefore, it can be argued that targeting key components of myocellular transcriptional machinery is sufficient to trigger necessary physiologic changes to mimic exercise and increase performance. Whether and how muscular remodeling resets the metabolic status of other organs is a matter of speculation. One possibility is that skeletal muscle remodeling may have retrograde adaptive effects in other metabolic tissues to enable energy efficiency. For example, muscle-derived myokines may exert "near-sited" (muscle vascularization) or "far-sited" (e.g., improved cardiac or pulmonary energetics) effects that contribute to the enhanced endurance. This speculation is relevant as exercise is known to trigger synthesis and secretion of muscle-derived myokines (e.g., IL-6) that exert extramuscular effects (40).

In contrast to tissue-specific genetic targeting, the endurance enhancement by synthetic activation of PPARδ, AMPK, and SIRT1 likely involves a multiple-organ effect, as these regulators are expressed and known to play a role in various tissues. For example, the cardiac expressions of AMPK and PPARδ are essential for normal functioning of the heart. Genetic inactivation of both AMPK and PPARδ in the heart leads to repressed oxidative metabolism and cardiac abnormalities (44,58). Further, activation of either AMPK with metformin (19) or PPARδ with GW0742 (47) provides cardioprotection against ischemia and pathologic hypertrophy. Exercise activates AMPK in the adipose tissue to drive fat oxidation and lipolysis (52). Likewise, transgenic activation of PPARδ increases fatty acid oxidation and thermogenesis in adipocytes to shrink fat (54). Therefore, the pharmacologic actions of the these agents in extramuscular tissues such as heart, fat, brain, liver, and vasculature may be essential for the exercise mimetic effects.

In summary, multiple distinct but converging signaling pathways now have been identified that can be genetically and chemically targeted to mirror exercise in the context of aerobic performance (Fig.). Whether these pathways can be classified as true "exercise mimetics" is a topic of intense debate (7,18). While it may be ambitious to expect these drugs to mimic all aspects of exercise, they do replicate the most cardinal exercise adaptation, that is, stimulating aerobic metabolism. The studies reviewed here clearly demonstrate the exercise mimetic effects of these drugs on endurance, obesity, diabetes, and cardiac health - the key benefits of regular exercise that are in urgent need of synthetic replication. Future studies will determine the therapeutic effects of the pathway-specific drugs alone or in combination with physical activity in various other diseases known to benefit from exercise.

Figure. Exe

Figure. Exe

We acknowledge that multiple groups have contributed to the understanding of signaling in the skeletal muscle. However, we are unable to cite all original work because of limitations on the number of references. Instead, we have cited comprehensive reviews for the introduction to each pathway.

This study was supported in part by a Ruth L. Kirschstein National Research Service Award from NIAMS (AR053803-03) to V.A.N.

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