Abstract
Duchenne muscular dystrophy (DMD) is the most prevalent inherited childhood muscle disorder in humans. mdx mice exhibit a similar pathophysiology to the human disorder allowing for an in-depth investigation of DMD. Myogenin, a myogenic regulatory factor, is best known for its role in embryonic myogenesis, but its role in adult muscle maintenance and regeneration is still poorly understood. Here, we generated an mdx:Myog flox/flox mouse harboring a tamoxifen-inducible Cre recombinase transgene, which was used to conditionally delete Myog during adult life. After tamoxifen treatment, three groups of mice were created to study the effects of Myog deletion: mdx:Myog flox/flox mice (mdx), Myog flox/flox mice (wild-type), and mdx:Myog floxΔ/floxΔ:Cre-ER mice (mdx:Myog-deleted). mdx:Myog-deleted mice exhibited no adverse phenotype and behaved normally. When run to exhaustion, mdx:Myog-deleted mice demonstrated an enhanced capacity for exercise compared to mdx mice, running nearly as far as wild-type mice. Moreover, these mice showed the same signature characteristics of muscle regeneration as mdx mice. Unexpectedly, we found that myogenin was dispensable for muscle regeneration. Factors associated with muscle fatigue, metabolism, and proteolysis were significantly altered in mdx:Myog-deleted mice, and this might contribute to their increased exercise capacity. Our results reveal novel functions for myogenin in adult muscle and suggest that reducing Myog expression in other muscle disease models may partially restore muscle function.
Highlights
Duchenne muscular dystrophy (DMD) is the most prevalent childhood muscle disorder in humans, affecting 1 in 3,500 newborn males [1]
We found that the deletion of Myog in mdx mice did not exacerbate their DMD, indicating that Myog is dispensable for muscle regeneration in adult mdx mice
The discovery that Myog is required during embryonic mouse muscle development initially supported this view [16], and a number of subsequent studies have further suggested a role for Myog in adult muscle maintenance and regeneration [18,19,20,25,26,27]
Summary
Duchenne muscular dystrophy (DMD) is the most prevalent childhood muscle disorder in humans, affecting 1 in 3,500 newborn males [1]. DMD is a chronic muscle-wasting disease that leads to progressive muscle weakness and atrophy. It is caused by mutations within the dystrophin gene, a critical structural component of the muscle cell membrane [2]. Animal models for DMD include the mdx mouse, which has been studied extensively to better understand the molecular basis of the disease and to develop therapeutic strategies that might be applicable to humans [4,5,6,7,8,9,10]
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