Nitric Oxide Sustains Long-Term Skeletal Muscle Regeneration by Regulating Fate of Satellite Cells Via Signaling Pathways Requiring Vangl2 and Cyclic GMP

Abstract

Satellite cells are myogenic precursors that proliferate, activate, and differentiate on muscle injury to sustain the regenerative capacity of adult skeletal muscle; in this process, they self-renew through the return to quiescence of the cycling progeny. This mechanism, while efficient in physiological conditions does not prevent exhaustion of satellite cells in pathologies such as muscular dystrophy where numerous rounds of damage occur. Here, we describe a key role of nitric oxide, an important signaling molecule in adult skeletal muscle, on satellite cells maintenance, studied ex vivo on isolated myofibers and in vivo using the α-sarcoglycan null mouse model of dystrophy and a cardiotoxin-induced model of repetitive damage. Nitric oxide stimulated satellite cells proliferation in a pathway dependent on cGMP generation. Furthermore, it increased the number of Pax7+/Myf5− cells in a cGMP-independent pathway requiring enhanced expression of Vangl2, a member of the planar cell polarity pathway involved in the Wnt noncanonical pathway. The enhanced self-renewal ability of satellite cells induced by nitric oxide is sufficient to delay the reduction of the satellite cell pool during repetitive acute and chronic damages, favoring muscle regeneration; in the α-sarcoglycan null dystrophic mouse, it also slowed disease progression persistently. These results identify nitric oxide as a key messenger in satellite cells maintenance, expand the significance of the Vangl2-dependent Wnt noncanonical pathway in myogenesis, and indicate novel strategies to optimize nitric oxide-based therapies for muscular dystrophy. Stem Cells 2012; 30:197–209.

Angiogenic Impairment of the Vascular Endothelium

“…This is consistent with new evidence supporting the use of NO-donating drugs as therapeutic agents for muscle repair and muscular dystrophy. 8,[30][31][32] It is also consistent with other findings demonstrating that enhancing cGMP signaling improves contractile performance and myocardial metabolic status in the dystrophindeficient heart. 32 It has been shown that NO-donating drugs correct functional ischemia in the setting of muscular dystrophy both in animal models and in humans, by restoring normal blood flow regulation and response to vasoconstrictors.…”

Mitochondrial Quality Control as a Therapeutic Target

“…This also demonstrated better functional gain than L-arginine combined with deflazacort in mdx dystrophic mice (Archer et al, 2006). Another study reported that the NO-releasing drug molsidomine has therapeutic effects in dystrophic mice (Buono et al, 2012). The drug increased muscle fiber regeneration and enhanced muscle function by increasing satellite cell proliferation.…”

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

“…Hematopoietic stem cell sensitivity to the self-renewal effects of NO may decrease with cell age (99). In vitro, treatment with the NO donor linsidomine (3-morpholinosydnonimine, SIN-1) stimulated proliferation of muscle satellite cells (a precursor muscle cell type), and this was inhibited by concurrent treatment with L-NAME (20). Hematopoietic stem cells treated with an NO donor proliferated faster and had increased expression of the self-renewal transcription factor cMyc (183).…”