PGC-1α regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy

Handschin, Christoph; Kobayashi, Yvonne M.; Chin, Stephanie; Seale, Patrick; Campbell, Kevin P.; Spiegelman, Bruce M.

doi:10.1101/gad.1525107

Cited by 325 publications

(395 citation statements)

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“…Consistent with this notion, muscle-specific expression of PGC-1a or ERRg transgenes enhances mitochondrial oxidative capacity, ameliorates symptoms of diseases affecting muscle health, and delays age-related loss of muscle function (6)(7)(8)(9). Perm1 provides an alternate means for enhancing mitochondrial oxidative capacity, likely having overlapping but not identical actions to those of PGC-1a and ERRg.…”

Section: Ckmt2 Glut4 Cpt1b Fabp3mentioning

confidence: 80%

Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle

et al. 2015

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Skeletal muscle mitochondrial content and oxidative capacity are important determinants of muscle function and whole‐body health. Mitochondrial content and function are enhanced by endurance exercise and impaired in states or diseases where muscle function is compromised, such as myopathies, muscular dystrophies, neuromuscular diseases, and age‐related muscle atrophy. Hence, elucidating the mechanisms that control muscle mitochondrial content and oxidative function can provide new insights into states and diseases that affect muscle health. In past studies, we identified Perm1 (PPARGC1‐ and ESRR‐induced regulator, muscle 1) as a gene induced by endurance exercise in skeletal muscle, and regulating mitochondrial oxidative function in cultured myotubes. The capacity of Perm1 to regulate muscle mitochondrial content and function in vivo is not yet known. In this study, we use adeno‐associated viral (AAV) vectors to increase Perm1 expression in skeletal muscles of 4‐wk‐old mice. Compared to control vector, AAV1‐Perm1 leads to significant increases in mitochondrial content and oxidative capacity (by 40‐80%). Moreover, AAV1‐Perm1‐transduced muscles show increased capillary density and resistance to fatigue (by 33 and 31 %, respectively), without prominent changes in fiber‐type composition. These findings suggest that Perm1 selectively regulates mitochondrial biogenesis and oxidative function, and implicate Perm1 in muscle adaptations that also occur in response to endurance exercise.—Cho, Y., Hazen, B. C., Gandra, P. G., Ward, S. R., Schenk, S., Russell, A. P., Kralli, A. Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle. FASEB J. 30, 674‐687 (2016). http://www.fasebj.org

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Section: Ckmt2 Glut4 Cpt1b Fabp3mentioning

confidence: 80%

Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle

et al. 2015

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“…Importantly, in line with the mitochondrial decline, PGC‐1α expression decreases during muscle aging in different species, including humans (Ghosh et al., 2011; Kang, Chung, Diffee, & Ji, 2013; Short et al., 2005; Vina et al., 2009). Moreover, PGC‐1α improves various muscle disorders, for example, denervation‐induced fiber atrophy (Sandri et al., 2006) or Duchenne muscular dystrophy (Handschin, Kobayashi et al., 2007). Of note, conclusions about the function of PGC‐1α in the context of natural aging are difficult to extrapolate from premature aging models, for example, those with severe mitochondrial impairment.…”

Section: Introductionmentioning

confidence: 99%

PGC‐1α affects aging‐related changes in muscle and motor function by modulating specific exercise‐mediated changes in old mice

et al. 2017

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SummaryThe age‐related impairment in muscle function results in a drastic decline in motor coordination and mobility in elderly individuals. Regular physical activity is the only efficient intervention to prevent and treat this age‐associated degeneration. However, the mechanisms that underlie the therapeutic effect of exercise in this context remain unclear. We assessed whether endurance exercise training in old age is sufficient to affect muscle and motor function. Moreover, as muscle peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α) is a key regulatory hub in endurance exercise adaptation with decreased expression in old muscle, we studied the involvement of PGC‐1α in the therapeutic effect of exercise in aging. Intriguingly, PGC‐1α muscle‐specific knockout and overexpression, respectively, precipitated and alleviated specific aspects of aging‐related deterioration of muscle function in old mice, while other muscle dysfunctions remained unchanged upon PGC‐1α modulation. Surprisingly, we discovered that muscle PGC‐1α was not only involved in improving muscle endurance and mitochondrial remodeling, but also phenocopied endurance exercise training in advanced age by contributing to maintaining balance and motor coordination in old animals. Our data therefore suggest that the benefits of exercise, even when performed at old age, extend beyond skeletal muscle and are at least in part mediated by PGC‐1α.

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“…The neuromuscular junction program is regulated by PGC-1a. 69 Furthermore, the activity of calcium-dependent signaling pathways via prolongation of myoplasmic calcium transients is increased by PGC-1a and similarly PGC-1a activates the transcription of nitric oxide synthase (inducible and endothelial, but not neuronal), which promotes elevated levels of nitric oxide. 35,70 By contrast, some other upstream activators, namely AMPK and p38 are not affected by ectopic expression of PGC-1a.…”

Section: Introductionmentioning

confidence: 99%

PGC-1α and exercise in the control of body weight

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Handschin

2012

Int J Obes

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The increasing prevalence of obesity and its comorbidities represents a major threat to human health globally. Pharmacological treatments exist to achieve weight loss, but the subsequent weight maintenance is prone to fail in the long run. Accordingly, efficient new strategies to persistently control body weight need to be elaborated. Exercise and dietary interventions constitute classical approaches to reduce and maintain body weight, yet people suffering from metabolic diseases are often unwilling or unable to move adequately. The administration of drugs that partially mimic exercise adaptation might circumvent this problem by easing and supporting physical activity. The thermogenic peroxisome proliferator-activated receptor g coactivator 1a (PGC-1a) largely mediates the adaptive response of skeletal muscle to endurance exercise and is a potential target for such interventions. Here, we review the role of PGC-1a in mediating exercise adaptation, coordinating metabolic circuits and enhancing thermogenic capacity in skeletal muscle. We suggest a combination of elevated muscle PGC-1a and exercise as a modified approach for the efficient long-term control of body weight and the treatment of the metabolic syndrome.International Journal of Obesity (2012) 36, 1428 --1435; doi:10.1038/ijo.2012.12; published online 31 January 2012Keywords: PGC-1a; thermogenesis; energy expenditure; exercise; weight control INTRODUCTION Metabolic disorders are increasingly recognized as major threats to public health. Almost two-thirds of the adult Americans are already overweight (body mass index 425 kg m --2 ) and the prevalence will presumably rise in the future. 1 Projections indicate that 86.3% of the adult American population will be overweight and 51.1% will even have to be classified as obese (body mass index 430 kg m --2 ) by the year 2030. 2 Importantly, excessive body weight fosters the development of comorbidities such as hypertension, dyslipidemia, cancer, cardiovascular disease and diabetes. 3,4 A protracted energy imbalance where energy intake exceeds expenditure is considered as a key element in the etiology of metabolic impairments. 5,6 Reducing energy intake (by nutritional intervention), increasing energy expenditure (by physical activity) or the combination of both thus constitute cornerstones in the treatment of metabolic disorders. 7 Such lifestyle interventions generally lead to weight loss initially 7 and improve metabolic parameters, 8 but the majority of patients regain their weight in the long run. 9,10 A meta-analysis of studies published between 1931 and 1999 reveals a median success rate to maintain body weight after weight loss of a moderate 15%. 11 This impressive recidivism rate after otherwise successful weight loss is partially due to poor adherence to lifestyle interventions and potently facilitated by coordinate actions of ancestral physiological responses designed to powerfully defend and restore body energy stores. 12 Indeed, weight loss initiated by reduced energy intake rapidly turns on a 'thrift...

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PGC-1α regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy

Cited by 325 publications

References 53 publications

Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle

Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle

PGC‐1α affects aging‐related changes in muscle and motor function by modulating specific exercise‐mediated changes in old mice

PGC-1α and exercise in the control of body weight

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