Sirtuin 1-mediated Effects of Exercise and Resveratrol on Mitochondrial Biogenesis

Menzies, Keir J.; Singh, Kuldeep; Saleem, Ayesha; Hood, David A.

doi:10.1074/jbc.m112.431155

Cited by 143 publications

(151 citation statements)

References 57 publications

(63 reference statements)

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“…RSV is known to improve energy homeostasis [16] and so we hypothesized that the mechanism of the positive effects of RSV on the myogenicity of satellite cells is linked to mitochondrial function. This hypothesis also implies that a decline in mitochondrial activity is one of the key causes of poor regenerative performance of muscle stem cells in a diabetic environment.…”

Section: Mitochondrial Membrane Potential Is Diminished In Muscle Stementioning

confidence: 99%

“…One of the targets of Sirt1 is PGC-1α, which positively regulates mitochondrial biogenesis and function. Interestingly, studies in mice with a muscle-specific Sirt1 knockout suggest that Sirt1 is not involved in RSV-induced mitochondrial biogenesis in muscle cells, indicating that other targets of RSV must be responsible for the positive effects of RSV on skeletal muscle metabolism [16].…”

Section: Introductionmentioning

confidence: 99%

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Sirt1-Independent Rescue of Muscle Regeneration by Resveratrol in Type I Diabetes

Conboy¹

2013

J Diabetes Metab

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Section: Mitochondrial Membrane Potential Is Diminished In Muscle Stementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sirt1-Independent Rescue of Muscle Regeneration by Resveratrol in Type I Diabetes

Conboy¹

2013

J Diabetes Metab

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“…Subsequent and parallel work of others has further solidified this theory (2,5,6,17,26,31,40,57). Studies aimed at deciphering the mechanisms involved in controlling the slow, oxidative phenotype in dystrophic skeletal muscle are important as they pave the way for target identification and rational design of specific interventions focused on ameliorating the pathology of DMD via pharmacological agents.Chronic administration of the naturally occurring polyphenol resveratrol (RSV) to numerous experimental, nondystrophic rodent models has revealed that this compound elicits the slow, oxidative myogenic program in skeletal muscle and ameliorates myopathies associated with high-fat feeding and muscle unloading, potentially through an AMPK-sirtuin 1 (SIRT1)-peroxisome proliferator-activated receptor-␥ coactivator-1␣ (PGC-1␣)-dependent web of intracellular signaling (1,3,4,14,18,30,33,34,35,42,45,49,52,59). Notably, this latter point is cause for debate (24,25,28,50,51,61).…”

mentioning

confidence: 99%

Resveratrol induces expression of the slow, oxidative phenotype in mdx mouse muscle together with enhanced activity of the SIRT1-PGC-1α axis

Ljubicic

Burt

Lunde

et al. 2014

American Journal of Physiology-Cell Physiology

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Ljubicic V, Burt M, Lunde JA, Jasmin BJ. Resveratrol induces expression of the slow, oxidative phenotype in mdx mouse muscle together with enhanced activity of the SIRT1-PGC-1␣ axis. Am J Physiol Cell Physiol 307: C66 -C82, 2014. First published April 24, 2014; doi:10.1152/ajpcell.00357.2013.-Slower, more oxidative muscle fibers are more resistant to the dystrophic pathology in Duchenne muscular dystrophy (DMD) patients as well as in the preclinical mdx mouse model of DMD. Therefore, one therapeutic strategy for DMD focuses on promoting expression of the slow, oxidative myogenic program. In the current study, we explored the therapeutic potential of stimulating the slow, oxidative phenotype in mdx mice by feeding 6-wk-old animals with the natural phenol resveratrol (RSV; ϳ100 mg·kg Ϫ1 ·day Ϫ1 ) for 6 wk. Sirtuin 1 (SIRT1) activity and protein levels increased significantly, as well as peroxisome proliferatoractivated receptor-␥ coactivator-1␣ (PGC-1␣) activity, in the absence of alterations in AMPK signaling. These adaptations occurred concomitant with evidence of a fast, glycolytic, to slower, more oxidative fiber type conversion, including mitochondrial biogenesis and increased expression of slower myosin heavy chain isoforms. These positive findings raised the question of whether increased exposure to RSV would result in greater therapeutic benefits. We discovered that an elevated RSV dose of ϳ500 mg·kg Ϫ1 ·day Ϫ1 across a duration of 12 wk was clearly less effective at muscle remodeling in mdx mice. This treatment protocol failed to influence SIRT1 or AMPK signaling and did not result in a shift towards a slower, more oxidative phenotype. Taken together, this study demonstrates that RSV can stimulate SIRT1 and PGC-1␣ activation, which in turn may promote expression of the slow, oxidative myogenic program in mdx mouse muscle. The data also highlight the importance of selecting an appropriate dosage regimen of RSV to maximize its potential therapeutic effectiveness for future application in DMD patients. DMD; SIRT1; utrophin A; PGC-1␣; AMPK DUCHENNE MUSCULAR DYSTROPHY (DMD) is a life-limiting, progressive muscle wasting disease that causes the loss of muscle function and independence. Genetic disruption of the dystrophin gene prevents the synthesis of the full-length dystrophin protein in skeletal muscle, which is the primary cause of the pathology (53). In the absence of dystrophin, the recruitment of the dystrophin-associated protein complex to the sarcolemma is impaired thereby creating a pathophysiological cascade with numerous adverse downstream events, including compromised sarcolemmal integrity, increased intracellular calcium, defective mitochondrial morphology, myofibrillar degradation, and ultimately death of the fibers (12). Over time, repeated cycles of muscle degeneration/regeneration result in the exhaustion of the muscle progenitor pool and the failure of regenerative capacity. Multiple experimental approaches to treat DMD are currently under investigation, including exon skipping and stop codo...

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“…Skeletal muscle mitochondrial function (Yamamoto et al ., 2011), mitochondrial biogenesis (Irrcher et al ., 2003), and resistance to oxidative stress (Nishiyama et al ., 1998; Fisher‐Wellman et al ., 2009; Ryan et al ., 2010) were also examined, as these mechanisms mediate exercise performance (Rockl et al ., 2007). The SIRT1, FOXO3a, and MEK pathways, key to mitochondrial biogenesis and protection against oxidative stress, were also examined (Wu et al ., 1999; Lagouge et al ., 2006; Gurd et al ., 2009; Menzies et al ., 2013; Li et al ., 2015; Smith et al ., 2015). As one of the most potent mechanisms limiting longevity is increased oxidative stress (Gemma et al ., 2007), MnSOD levels were examined and exercise was examined in AC5 KO mice mated with MnSOD heterozygous ( MnSOD +/− ) mice.…”

Section: Introductionmentioning

confidence: 99%

Type 5 adenylyl cyclase disruption leads to enhanced exercise performance

et al. 2015

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SummaryThe most important physiological mechanism mediating enhanced exercise performance is increased sympathetic, beta adrenergic receptor (β‐AR), and adenylyl cyclase (AC) activity. This is the first report of decreased AC activity mediating increased exercise performance. We demonstrated that AC5 disruption, that is, knock out (KO) mice, a longevity model, increases exercise performance. Importantly for its relation to longevity, exercise was also improved in old AC5 KO. The mechanism resided in skeletal muscle rather than in the heart, as confirmed by cardiac‐ and skeletal muscle‐specific AC5 KO's, where exercise performance was no longer improved by the cardiac‐specific AC5 KO, but was by the skeletal muscle‐specific AC5 KO, and there was no difference in cardiac output during exercise in AC5 KO vs. WT. Mitochondrial biogenesis was a major mechanism mediating the enhanced exercise. SIRT1, FoxO3a, MEK, and the anti‐oxidant, MnSOD were upregulated in AC5 KO mice. The improved exercise in the AC5 KO was blocked with either a SIRT1 inhibitor, MEK inhibitor, or by mating the AC5 KO with MnSOD hetero KO mice, confirming the role of SIRT1, MEK, and oxidative stress mechanisms. The Caenorhabditis elegans worm AC5 ortholog, acy‐3 by RNAi, also improved fitness, mitochondrial function, antioxidant defense, and lifespan, attesting to the evolutionary conservation of this pathway. Thus, decreasing sympathetic signaling through loss of AC5 is not only a mechanism to improve exercise performance, but is also a mechanism to improve healthful aging, as exercise also protects against diabetes, obesity, and cardiovascular disease, which all limit healthful aging.

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Sirtuin 1-mediated Effects of Exercise and Resveratrol on Mitochondrial Biogenesis

Cited by 143 publications

References 57 publications

Sirt1-Independent Rescue of Muscle Regeneration by Resveratrol in Type I Diabetes

Sirt1-Independent Rescue of Muscle Regeneration by Resveratrol in Type I Diabetes

Resveratrol induces expression of the slow, oxidative phenotype in mdx mouse muscle together with enhanced activity of the SIRT1-PGC-1α axis

Type 5 adenylyl cyclase disruption leads to enhanced exercise performance

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