A therapeutic approach for Duchenne muscular dystrophy (DMD) is to up-regulate utrophin in skeletal muscle in an effort to compensate for the lack of dystrophin. We previously hypothesized that promotion of the slow, oxidative myogenic program, which triggers utrophin up-regulation, can attenuate the dystrophic pathology in mdx animals. Since treatment of healthy mice with the AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) enhances oxidative capacity and elicits a fast-to-slow fiber-type transition, we evaluated the effects of chronic AMPK stimulation on skeletal muscle phenotype and utrophin expression in mdx mice. Daily AICAR administration (500 mg/kg/day, 30 days) of 5-7-week-old mdx animals induced an elevation in mitochondrial cytochrome c oxidase enzyme activity, an increase in myosin heavy-chain type IIa-positive fibers and slower twitch contraction kinetics in the fast, glycolytic extensor digitorum longus muscle. Utrophin expression was significantly enhanced in response to AICAR, which occurred coincident with an elevated β-dystroglycan expression along the sarcolemma. These adaptations were associated with an increase in sarcolemmal structural integrity under basal conditions, as well as during damaging eccentric contractions ex vivo. Notably, peroxisome proliferator-activated receptor γ co-activator-1α (PGC-1α) and silent information regulator two ortholog 1 protein contents were significantly higher in muscle from mdx mice compared with wild-type littermates and AICAR further increased PGC-1α expression. Our data show that AICAR-evoked muscle plasticity results in beneficial phenotypic adaptations in mdx mice and suggest that the contextually novel application of this compound for muscular dystrophy warrants further study.

Duchenne muscular dystrophy (DMD) is a life-limiting, neuromuscular disorder that causes progressive, severe muscle wasting in boys and young men. Although there is no cure, scientists and clinicians can leverage the fact that slower, more oxidative skeletal muscle fibers possess an enhanced degree of resistance to the dystrophic pathology relative to their faster, more glycolytic counterparts, and can thus use this knowledge when investigating novel therapeutic avenues. Several factors have been identified as powerful regulators of muscle plasticity. Some proteins, such as calcineurin, peroxisome proliferator-activated receptor (PPAR) γ coactivator 1α (PGC-1α), PPARβ/δ, and AMP-activated protein kinase (AMPK), when chronically stimulated in animal models, remodel skeletal muscle toward the slow, oxidative myogenic program, whereas others, such as receptor-interacting protein 140 (RIP140) and E2F transcription factor 1 (E2F1), repress this phenotype. Recent studies demonstrating that pharmacologic and physiological activation of targets that shift dystrophic muscle toward the slow, oxidative myogenic program provide appreciable molecular and functional benefits. This review surveys the rationale behind, and evidence for, the study of skeletal muscle plasticity in preclinical models of DMD and highlights the potential therapeutic opportunities in advancing a strategy focused on remodeling skeletal muscle in patients with DMD toward the slow, oxidative phenotype.

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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