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Does SIRT1 determine exercise-induced skeletal muscle mitochondrial biogenesis: differences between in vitro and in vivo experiments?

2011; American Physiological Society; Volume: 112; Issue: 5 Linguagem: Inglês

10.1152/japplphysiol.01262.2011

8750-7587

Brendon J. Gurd, Jonathan P. Little, Christopher G. R. Perry,

Autophagy in Disease and Therapy

ViewpointPerspectivesDoes SIRT1 determine exercise-induced skeletal muscle mitochondrial biogenesis: differences between in vitro and in vivo experiments?Brendon J. Gurd, Jonathan P. Little, and Christopher G. R. PerryBrendon J. GurdSchool of Kinesiology and Health Studies, Queen's University, Kingston, Ontario; , Jonathan P. LittleDepartment of Biology, I.K. Barber School of Arts and Sciences, University of British Columbia Okanagan, Kelowna, British Columbia; and , and Christopher G. R. PerryDepartment of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, CanadaPublished Online:01 Mar 2012https://doi.org/10.1152/japplphysiol.01262.2011This is the final version - click for previous versionMoreSectionsPDF (49 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat in 2007, Gerhart-Hines et al. (12) published a series of cell culture experiments that implicated Sirtuin-1 (SIRT1) in the regulation of mitochondrial content and fatty acid oxidation in skeletal muscle. Specifically, this study proposed that SIRT1 deacetylates peroxisome proliferator-activated receptor γ coactivator (PGC)-1α, resulting in increased transcription of genes associated with mitochondrial metabolism and fatty acid utilization. This model has since been implicated in the mitochondrial adaptive response to exercise, with SIRT1 functioning as a metabolic sensor in skeletal muscle (for review, see Refs. 2, 27). In this Viewpoint we will discuss the evidence for and against the regulation of PGC-1α by SIRT1, as proposed by Gerhart-Hines et al. (12), particularly with respect to exercise-induced mitochondrial biogenesis. Although the effects of SIRT1 have been eloquently demonstrated in vitro (4, 12, 32), the involvement of SIRT1 in the activation of PGC-1α-mediated transcription in vivo appears more complex than originally hypothesized.Activation of SIRT1: Is SIRT1 Involved in Pharmacological Induction of Mitochondrial Biogenesis in Skeletal Muscle?Much of the original support for a positive effect of SIRT1 on mitochondrial function in skeletal muscle comes from the demonstration that pharmacological activation of SIRT1 using resveratrol and SRT1720 results in deacetylation of PGC-1α and improved mitochondrial content and fatty acid utilization in skeletal muscle in vivo (10, 20, 30). However, the specificity of resveratrol and SRT1720 has been questioned (29) and these activators appear to target AMPK in addition to (1), and perhaps independently of (6), SIRT1. Given that AMPK can directly phosphorylate PGC-1α and that activation of AMPK is intimately linked with mitochondrial biogenesis (18), these findings suggest that nonspecific AMPK activation may underlie mitochondrial biogenesis (and PGC-1α activation) with resveratrol and SRT1720 treatments. In support of this contention, AMPK is required for resveratrol-induced deacetylation and activation of PGC-1α following fasting and acute exercise in mice (5, 37). Furthermore, evidence suggests that anti-inflammatory and neuroprotective effects of resveratrol are mediated by AMPK and not SIRT1 (6, 9). It is also unknown if acute treatment with resveratrol or SRT1720 will increase SIRT1 activity in vivo to cause acute, short term, activation of PGC-1α. It should be noted that SIRT1 was required for AICAR-induced deacetylation of transfected PGC-1α in C2C12 myocytes. In addition, SIRT1 is implicated in acute activation of AMPK in various cell lines (17, 21, 39). Combined these results suggest that AMPK and SIRT1 function in concert to phosphorylate, deacetylate, and activate PGC-1α in cell culture experiments (5), providing evidence that pharmacological activation of the AMPK-SIRT1 axis contributes to regulation of mitochondrial biogenesis in skeletal muscle cells. However, the nonspecific action of resveratrol and SRT1720 and SIRT1-independent effects of these drugs in some models (6, 9) suggest that the relative contributions of SIRT1 in skeletal muscle in vivo remain unclear.Is there a Relationship Between SIRT1 and Mitochondrial Content in Skeletal Muscle?As chronic contractile activity is a potent stimulus for mitochondrial biogenesis, the application of the SIRT1/PGC-1α model to exercise training adaptations seems logical. Indeed, consistent with the SIRT1/PGC-1α pathway responding to exercise in skeletal muscle are reports that SIRT1 is activated (16) and PGC-1α is deacetylated and activated (4, 5) following an acute bout of exercise in rodents (see below for a discussion of potential mechanisms controlling SIRT1 activity). Furthermore, increases in skeletal muscle mitochondrial content, induced by chronic contractile activity, are accompanied by deacetylation of PGC-1α (23) and increases in SIRT1 deacetylase activity in both rodents (7, 15, 19) and humans (14). There are also reports that SIRT1 protein increases along with mitochondrial biogenesis in both rodents (25, 35) and humans (24). However, other reports have observed no relationship (7), or a negative relationship (15) between SIRT1 protein content and oxidative capacity across diverse fiber types in rodent muscle. Furthermore, decreases in SIRT1 protein content have been reported following chronic contractile activity in rodents (15) and exercise training in humans (14). Although there is some evidence that transient increases in SIRT1 protein contribute to the initiation of mitochondrial biogenesis (36), numerous reports suggest that a sustained increase in SIRT1 protein is not required for increases in mitochondrial content (7, 15, 16, 19).Surprisingly, overexpression of SIRT1 in rodent skeletal muscle was shown to reduce markers of mitochondrial content, suggesting that elevated SIRT1 protein may actually impair mitochondrial biogenesis (15). Also in agreement with a repressive effect of SIRT1 is a report that SIRT1 activity is increased while mitochondrial content is decreased in hindlimb muscle following denervation (7). Furthermore, direct evidence that SIRT1 is not required in exercise-induced PGC-1α-mediated muscle mitochondrial biogenesis was recently reported (31). These authors found unhindered mitochondrial biogenesis following exercise in mice lacking skeletal muscle SIRT1 deacetylase activity (31). Although this study did not examine the possibility of compensatory deacetylation by other Sirtuins [for example, both SIRT1 and SIRT2 deacetylate common targets (38)] their results do support redundancy in the pathways regulating PGC-1α acetylation and thus question the fundamental assumption that PGC-1α deacetylation by SIRT1 is required for its activation in skeletal muscle. Collectively, these findings indicate that SIRT1 content and/or activity are not necessarily required for exercise-induced muscle mitochondrial biogenesis in vivo and highlight the apparent incompatibilities between the clearly demonstrated biogenic effects of SIRT1 in vitro (3, 5, 12) and in vivo results.Exercise and SIRT1: Activating the ActivatorIt has been suggested that SIRT1 may act as a metabolic sensor via changes in cellular redox state (28, 32). Although not universal (33, 34), it is generally accepted that exercise results in a large increase in intramuscular NAD+ (5, 7, 13), which likely contributes to increases in SIRT1 activity. Furthermore, there is evidence that the NAD+ salvage pathway, controlled in part by an AMPK-Nampt axis, plays an important role in determining intramuscular NAD+ and therefore SIRT1 activity (11). Nampt protein content is associated with NAD+ in skeletal muscle (19) and is upregulated following both acute exercise in mice (5) and exercise training in humans (8). NAD+ regulation of SIRT1 suggests that deacetylase activity is determined by the metabolic environment rather than changes in SIRT1 protein content per se. This may help explain contradictory observations that SIRT1 protein content and deacetylase activity do not always correlate (7, 14, 15, 19); however, difficulties associated with measuring SIRT1 activity (e.g., specificity of commercially available SIRT1 assay kits and/or technical limitations associated with measuring PGC-1α acetylation in humans) must also be acknowledged. Although the regulation of SIRT1 activity in response to exercise requires further study, it is important that future studies assess SIRT1 deacetylase activity through direct measurement or via target protein acetylation status.In Vitro vs. In Vivo Results: Can We Explain Discrepant Observations?Although in vivo evidence supportive of a repressive role for SIRT1 on muscle mitochondrial content (7, 15) is difficult to reconcile, it is worth noting that both a fourfold overexpression of SIRT1 (15) and chronic muscle denervation (7) represent perturbations that are unlikely to occur naturally. These results aside, it is possible that inconsistencies between in vitro and in vivo studies discussed above may shed light on the physiological role of SIRT1. Specifically, we propose that SIRT1 plays an important role in the remodeling of predominantly glycolytic muscle—which tends to be more responsive to stimuli that induce mitochondrial biogenesis (15, 40)—toward a more oxidative phenotype. On one end of the continuum of oxidative capacity are muscle cell cultures, which are generally believed to be highly glycolytic (22, 26) and are also highly responsive to increases in SIRT1 protein (12, 32). This hypothesis appears to be supported in vivo by studies demonstrating that SIRT1 content is generally higher in less oxidative muscle (7, 14, 15) and that PGC-1α is deacetylated to a greater extent in less oxidative muscle following exercise (4). Although speculative at this point, this hypothesis may help to reconcile in vitro results that clearly demonstrate a positive effect of SIRT1 on mitochondrial biogenesis, with the less consistent observations reported in vivo (especially in human muscle samples with mixed fiber types).SIRT1 in Skeletal Muscle: Still Much to LearnA role for SIRT1 in regulating mitochondrial content in skeletal muscle through deacetylation of nuclear PGC-1α is supported by ample evidence from cell culture work (4, 5, 12, 32). However, in vivo studies where SIRT1 is overexpressed (15) or knocked out (31) are not supportive of this relationship. Specifically, the importance of SIRT1 in exercise-induced mitochondrial biogenesis in vivo is unclear given the considerable inconsistency surrounding the relationship between SIRT1 protein, SIRT1 activity, and changes in mitochondrial content (7, 14, 15, 24, 31, 35). Although we have proposed a potential role for SIRT1 in the determination of muscle remodeling in predominantly glycolytic muscle, there is a clear need for further elucidation of the role of SIRT1 biology in skeletal muscle and in exercise-induced mitochondrial biogenesis in vivo. Future work examining the activity, regulators, and target proteins of this enzyme, with a focus on fiber-type specific responses, may be required to fully understand SIRT1 function.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors.AUTHOR CONTRIBUTIONSAuthor contributions: B.J.G., J.P.L., and C.G.P. conception and design of research; B.J.G., J.P.L., and C.G.P. drafted manuscript; B.J.G., J.P.L., and C.G.P. edited and revised manuscript; B.J.G., J.P.L., and C.G.P. approved final version of manuscript.REFERENCES1. 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White, and Simon Schenk1 August 2012 | American Journal of Physiology-Endocrinology and Metabolism, Vol. 303, No. 3 More from this issue > Volume 112Issue 5March 2012Pages 926-928 Copyright & PermissionsCopyright © 2012 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.01262.2011PubMed22096123History Received 11 October 2011 Accepted 16 November 2011 Published online 1 March 2012 Published in print 1 March 2012 Metrics