Sonic hedgehog gene therapy increases the ability of the dystrophic skeletal muscle to regenerate after injury

Abstract

The Hedgehog (Hh) pathway is a crucial regulator of muscle development during embryogenesis. We have previously demonstrated that Sonic hedgehog (Shh) regulates postnatal myogenesis in the adult skeletal muscle both directly, by acting on muscle satellite cells, and indirectly, by promoting the production of growth factors from interstitial fibroblasts. Here, we show that in mdx mice, the murine equivalent of Duchenne muscular dystrophy in humans, progression of the dystrophic pathology corresponds to progressive inhibition of the Hh signaling pathway in the skeletal muscle. We also show that the upregulation of the Hh pathway in response to injury and during regeneration is significantly impaired in mdx muscle. Shh treatment increases the proliferative potential of satellite cells isolated from the muscles of mdx mice. This treatment also increases the production of proregenerative factors, such as insulin-like growth factor-1 and vascular endothelial growth factor, from fibroblasts isolated from the muscle of mdx mice. In vivo, overexpression of the Hh pathway using a plasmid encoding the human Shh gene promotes successful regeneration after injury in terms of increased number of proliferating myogenic cells and newly formed myofibers, as well as enhanced vascularization and decreased fibrosis.

Protective Effects of Sonic Hedgehog Against Ischemia/Reperfusion Injury in Mouse Skeletal Muscle via AKT/mTOR/p70S6K Signaling

“…However, clear but not sustained Shh expression was induced in skeletal muscle after I/R injury. Comparable results were recently observed in other experimental models, including a cardiotoxin (CTX)-induced injury model [27], skeletal muscle mechanical crush model [21] and hindlimb ischemia model [20]. All of the above studies and our data collectively indicate that Shh, an important regulator in embryo development, is recruited postnatally in specific pathological conditions.…”

“…Moreover, in the present study we also observed that up-regulation of Gli1 and Gli2 accompanied the Shh response to I/R injury. Among the Glis, Gli1 is the principal transcription factor in the Shh pathway, and many studies have shown that it is of great importance in skeletal muscle regeneration [20, 27, 28]. Furthermore, Gli2 activity has been confirmed to be sufficient and required for efficient MyoD treatment during skeletal myogenesis [29], which plays a major role in regulating muscle differentiation during embryogenesis and adult muscle regeneration [30].…”

Management of Cutaneous and Extracutaneous Side Effects of Smoothened Inhibitor Therapy for Advanced Basal Cell Carcinoma

“…The mechanism of myopathy in humans taking SIs has not been established. In animal models, activation of the Shh pathway promotes regeneration of myofibers (25,29,31); therefore, inhibition of the pathway with SIs may impede muscle repair.…”

“…Although there is no clear association between muscle spasm or myalgia symptoms and CK elevations, it could be hypothesized that CK elevation may result from impaired repair of cellular muscle damage, as discussed in the section on myopathy (29,31).…”

“…Nevertheless, data on the function of the Hh pathway from preclinical animal models and the limited clinical trials in humans lend insight into how SIs may exert their toxicities (8,(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). While data are still being collected on side effects specific to individual SIs, several side effects, such as hair loss, muscle spasms, and gastrointestinal (GI) and taste disturbances, are common to several SIs and are likely class effects.…”