An inhibitor of transforming growth factor beta type I receptor ameliorates muscle atrophy in a mouse model of caveolin 3-deficient muscular dystrophy

Abstract

Skeletal muscle expressing Pro104Leu mutant caveolin 3 (CAV3 P104L ) in mouse becomes atrophied and serves as a model of autosomal dominant limb-girdle muscular dystrophy 1C. We previously found that caveolin 3-deficient muscles showed activated intramuscular transforming growth factor beta (TGF-b) signals. However, the cellular mechanism by which loss of caveolin 3 leads to muscle atrophy is unknown. Recently, several small-molecule inhibitors of TGF-b type I receptor (TbRI) kinase have been developed as molecular-targeting drugs for cancer therapy by suppressing intracellular TGF-b1, -b2, and -b3 signaling. Here, we show that a TbRI kinase inhibitor, Ki26894, restores impaired myoblast differentiation in vitro caused by activin, myostatin, and TGF-b1, as well as CAV3 P104L . Oral administration of Ki26894 increased muscle mass and strength in vivo in wild-type mice, and improved muscle atrophy and weakness in the CAV3 P104L mice. The inhibitor restored the number of satellite cells, the resident stem cells of adult skeletal muscle, with suppression of the increased phosphorylation of Smad2, an effector, and the upregulation of p21 (also known as Cdkn1a), a target gene of the TGF-b family members in muscle. These data indicate that both TGF-b-dependent reduction in satellite cells and impairment of myoblast differentiation contribute to the cellular mechanism underlying caveolin 3-deficient muscle atrophy. TbRI kinase inhibitors could antagonize the activation of intramuscular anti-myogenic TGF-b signals, thereby providing a novel therapeutic rationale for the alternative use of this type of anticancer drug in reversing muscle atrophy in various clinical settings.

GDF11 Does Not Rescue Aging-Related Pathological Hypertrophy

“…A recent study suggests that disease-free aging induces pathological cardiac hypertrophy (PCH) in 24-month-old mice and that this results in large part from an age-related reduction in the circulating blood levels of G rowth D ifferentiation F actor 11 (GDF11), a member of the Transforming Growth Factor β (TGFβ) super family of cytokines 1 . GDF11 and related family members generally reduce skeletal muscle protein synthesis and repair and enhance protein degradation, which leads to muscle atrophy in adults 2, 3 . Loss of these factors, particularly myostatin (also called GDF8) 4, 5 is primarily associated with skeletal muscle hypertrophy but with limited effects on the heart 6 .…”

Apocynin inhibits the upregulation of TGF-β1 expression and ROS production induced by TGF-β in skeletal muscle cells

“…Thus, our data are in agreement with these reports since they indirectly suggest that the fibrotic effect mediated by TGF-β could require ROS in skeletal muscle. Interestingly, TGF-β also produces skeletal muscle atrophy, as has been recently reported (Mendias et al, 2012;Narola et al, 2013;Ohsawa et al, 2012;Zhang et al, 2014). However, the molecular mechanism and signalling pathways that are involved have not been elucidated yet.…”

MURC/cavin-4 Is Co-Expressed with Caveolin-3 in Rhabdomyosarcoma Tumors and Its Silencing Prevents Myogenic Differentiation in the Human Embryonal RD Cell Line

“…MURC/CAVIN-4 gene knock-down or over-expression has been shown to impair or improve the differentiation of mouse C2C12 myoblasts through decreased or increased ERK1/2 activation in the later stages of differentiation [51]. Cav-3 is a membrane scaffolding protein [61–63] that interacting at the sarcolemma with a number of signalling proteins, such as nitric oxide synthase [64, 65], TGF-β (transforming growth factor-beta) receptors [66, 67] and dysferlin [68, 69], is involved in the regulation of many processes, including skeletal muscle differentiation and regeneration. Mutated Cav-3 forms affect the survival and differentiation of myoblasts [70, 71] and are involved in the onset of cardiac and neuromuscular disorders [72–75], such as the Limb Girdle Muscular Dystrophy 1-C [64, 65, 76, 77].…”