The therapeutic potential of skeletal muscle plasticity in Duchenne muscular dystrophy: phenotypic modifiers as pharmacologic targets

V Ljubicic, M Burt, BJ Jasmin - The FASEB Journal, 2014 - Wiley Online Library
The FASEB Journal, 2014Wiley Online Library
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 …
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., Jasmin, B. J. The therapeutic potential of skeletal muscle plasticity in Duchenne muscular dystrophy: phenotypic modifiers as pharmacologic targets. FASEB J. 28, 548–568 (2014). www.fasebj.org
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