Abstract
Muscular dystrophies are severe disorders due to mutations in structural genes, and are characterized by skeletal muscle wasting, compromised patient mobility, and respiratory functions. Although previous works suggested enhancing regeneration and muscle mass as therapeutic strategies, these led to no long-term benefits in humans. Mice lacking the transcription factor Nfix have delayed regeneration and a shift toward an oxidative fiber type. Here, we show that ablating or silencing the transcription factor Nfix ameliorates pathology in several forms of muscular dystrophy. Silencing Nfix in postnatal dystrophic mice, when the first signs of the disease already occurred, rescues the pathology and, conversely, Nfix overexpression in dystrophic muscles increases regeneration and markedly exacerbates the pathology. We therefore offer a proof of principle for a novel therapeutic approach for muscular dystrophies based on delaying muscle regeneration.
Highlights
Muscular dystrophies are severe disorders due to mutations in structural genes, and are characterized by skeletal muscle wasting, compromised patient mobility, and respiratory functions
Muscular dystrophies (MDs) are inherited skeletal muscle disorders characterized by progressive muscle damage and weakness of variable distribution and severity, leading to wheelchair dependency and, in the most severe cases, to patient’s death[1, 2]
The most common form is Duchenne muscular dystrophy (DMD), an X-linked autosomal recessive disorder due to mutations in the dystrophin gene, which encodes a protein anchoring the sarcolemmal membrane to the cytoskeleton, protecting the fibers from contraction-induced damage[3]
Summary
Muscular dystrophies are severe disorders due to mutations in structural genes, and are characterized by skeletal muscle wasting, compromised patient mobility, and respiratory functions. The most common form is Duchenne muscular dystrophy (DMD), an X-linked autosomal recessive disorder due to mutations in the dystrophin gene, which encodes a protein anchoring the sarcolemmal membrane to the cytoskeleton, protecting the fibers from contraction-induced damage[3]. We show that silencing Nfix in both α-sarcoglycan (Sgca null)- and dystrophin (mdx)-deficient dystrophic mice strikingly protects from the degenerative process by promoting a more oxidative musculature and by slowing down muscle regeneration, in contrast to previous attempts that aimed to promote regeneration These data are supportive of a new role for Nfix in the progression of MD and suggest Nfix as a novel target to treat this severe disease. We provide proof of principle for an innovative therapeutic approach based on the idea that slowing down the degeneration–regeneration cycles, instead of increasing regeneration, delays the progression of the pathology
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