Abstract
BackgroundFibrosis, an excessive collagen accumulation, results in scar formation, impairing function of vital organs and tissues. Fibrosis is a hallmark of muscular dystrophies, including the lethal Duchenne muscular dystrophy (DMD), which remains incurable. Substitution of muscle by fibrotic tissue also complicates gene/cell therapies for DMD. Yet, no optimal models to study muscle fibrosis are available. In the widely used mdx mouse model for DMD, extensive fibrosis develops in the diaphragm only at advanced adulthood, and at about two years of age in the ‘easy-to-access’ limb muscles, thus precluding fibrosis research and the testing of novel therapies.MethodsWe developed distinct experimental strategies, ranging from chronic exercise to increasing muscle damage on limb muscles of young mdx mice, by myotoxin injection, surgically induced trauma (laceration or denervation) or intramuscular delivery of profibrotic growth factors (such as TGFβ). We also extended these approaches to muscle of normal non-dystrophic mice.ResultsThese strategies resulted in advanced and enhanced muscle fibrosis in young mdx mice, which persisted over time, and correlated with reduced muscle force, thus mimicking the severe DMD phenotype. Furthermore, increased fibrosis was also obtained by combining these procedures in muscles of normal mice, mirroring aberrant repair after severe trauma.ConclusionsWe have developed new and improved experimental strategies to accelerate and enhance muscle fibrosis in vivo. These strategies will allow rapidly assessing fibrosis in the easily accessible limb muscles of young mdx mice, without necessarily having to use old animals. The extension of these fibrogenic regimes to the muscle of non-dystrophic wild-type mice will allow fibrosis assessment in a wide array of pre-existing transgenic mouse lines, which in turn will facilitate understanding the mechanisms of fibrogenesis. These strategies should improve our ability to combat fibrosis-driven dystrophy progression and aberrant regeneration.
Highlights
Fibrosis, an excessive collagen accumulation, results in scar formation, impairing function of vital organs and tissues
Consistent with this, we found enhanced levels of active Smad2/3 (Figure 1D) and Transforming growth factor-β (TGFβ) target genes such as Coll I, FN, tissue inhibitor of metalloproteinases 1 (TIMP-1) and connective tissue growth factor (CTGF), indicative of functional TGFβ signaling in fibrotic Duchenne muscular dystrophy (DMD) muscle (Figure 1E)
Collectively, through this study, we propose novel and/or optimized experimental strategies to accelerate, anticipate and boost muscle fibrosis in young dystrophic mice or to drive de novo fibrosis onset in WT mice
Summary
An excessive collagen accumulation, results in scar formation, impairing function of vital organs and tissues. Substitution of muscle by fibrotic tissue complicates gene/cell therapies for DMD. In the widely used mdx mouse model for DMD, extensive fibrosis develops in the diaphragm only at advanced adulthood, and at about two years of age in the ‘easy-to-access’ limb muscles, precluding fibrosis research and the testing of novel therapies. Duchenne muscular dystrophy (DMD) is one of the severest of the by fat and fibrotic tissue, leading to premature death in the late teens or early twenties from respiratory and cardiac failure [6]. The mdx mouse strain, the most widely used animal model for studying human DMD, has a nonsense mutation in dystrophin exon 23 leading to dystrophin protein absence [9].
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