Nitric Oxide Controls Fat Deposition in Dystrophic Skeletal Muscle by Regulating Fibro-Adipogenic Precursor Differentiation

Abstract

Duchenne muscular dystrophy (DMD) is an hereditary disease characterized by loss of muscle fibers and their progressive substitution by fat and fibrous tissue. Mesenchymal fibro-adipogenic progenitors (FAPs) expressing the platelet-derived growth factor receptor alpha (PDGFRa) are an important source of fibrosis and adipogenesis in dystrophic skeletal muscle. Among the therapies suggested for dystrophy are those based on nitric oxide (NO) donating drugs, the administration of which slows disease progression. NO has been shown to act by enhancing the regenerative potential of the diseased muscle. Whether it acts also by inhibiting fibrosis and adipogenesis was not known. Here, we show in vitro that NO regulates FAP fate through inhibition of their differentiation into adipocytes. In mdx mice, an animal model of DMD, treatment with the NO donating drug molsidomine reduced the number of PDGFRa 1 cells as well as the deposition of both skeletal muscle fat and connective tissues. Inhibition of adipogenesis was due to NO-induced increased expression of miR-27b leading to downregulation of peroxisome proliferator-activated receptors gamma (Pparc1) expression in a pathway independent of cGMP generation. These findings reveal an additional effect of NO in dystrophic muscle that conceivably synergizes with its known effects on regeneration improvement and explain why NO-based therapies appear effective in the treatment of muscular dystrophy. STEM CELLS 2014;32:874-885

Opposing roles of miR-21 and miR-29 in the progression of fibrosis in Duchenne muscular dystrophy

“…Other miRNAs have been shown to be important modulators of the dystrophic phenotype. For example, Cordani et al [8] recently showed that nitric oxide-induced upregulation of miR-27 was able to inhibit adipogenesis, which is an integral part of the fibrotic process.…”

Mammalian Skeletal Muscle Fibres Promote Non-Muscle Stem Cells and Non-Stem Cells to Adopt Myogenic Characteristics

“…Accumulation of fat tissue is a key feature of this condition, for example, in Duchenne Muscular Dystrophy, and is believed to hinder the activity of SC. [31,32]. However, our work reveals a more direct property of ADMSC that would contribute to muscle pathology, based on our finding that they induce fibre hyper-contraction.…”

Nutraceuticals and Their Potential to Treat Duchenne Muscular Dystrophy: Separating the Credible from the Conjecture

“…In the mdx mouse and DMD patients the loss of sarcolemmal nNOS results in a susceptibility to ischemia especially following mild exercise such as day-to-day limb movement. Additionally, localization of nNOS to the sarcolemma has been implicated in protection from the damaging effects of inflammation and oxidative stress, fat deposition, fibrosis and activation of satellite cells [73,229,230,231,232]. Under normal circumstances muscle derived nitric oxide (NO) attenuates the α-adrenergic vasoconstriction in exercised skeletal muscle which acts to optimize blood flow; this is referred to as functional sympatholysis [233,234,235].…”