Growth curves revealed that the double-mutant Tg mice were significantly larger than the mutant caveolin-3 Tg mice and similar in size to the wild-type mice beginning at 6 weeks until 16 weeks of age (42). The muscle atrophy seen in the mutant caveolin-3 Tg was reversed in the double-mutant Tg with increased myofiber size and myofiber number. Thus, myostatin PR-171 manufacturer inhibition reverses caveolin-3-deficient muscular atrophy in vivo. Caveolin-3-deficient muscle from mutant caveolin-3 Tg mice showed hyperphosphorylation

Inhibitors,research,lifescience,medical of an R-Smad of myostatin, Smad2 and significant upregulation of a myostatin target gene, p21. These in vivo findings

were consistent with our in vitro study in which caveolin-3 suppresses myostatin signaling. In the double-mutant Tg mouse, the levels of phospho-Smad2 and p21 gene expression were Inhibitors,research,lifescience,medical significantly reduced compared to those in the mutant caveolin-3 Tg mice and were similar to those in the wild-type mice. Thus, myostatin inhibition by genetic introduction of myostatin Inhibitors,research,lifescience,medical inhibitor normalized enhanced myostatin signaling and also reversed muscular phenotype in the caveolin-3 deficient mouse. Myostatin inhibition therapy reversed muscular Inhibitors,research,lifescience,medical atrophy in caveolin-3 deficiency We injected a soluble form of the extracellular domain of type II myostatin receptor,

ActRIIB, which can inhibit myostatin-its type II receptor binding (25, 44), into the mutant caveolin-3 Tg mice to develop myostatin inhibition through its type II receptor as a therapeutic strategy for patients with LGMD1C. Intraperitoneal injection of soluble ActRIIB Inhibitors,research,lifescience,medical four times significantly increased skeletal muscle mass and reversed myofiber hypotrophy accompanied with suppression of Smad2 phosphorylation and downregulation of p21. This finding, therefore, suggests that myostatin inhibition therapy may be a reasonable and promising therapy for caveolin-3-deficient muscular dystrophy associated with enhanced myostatin signaling. Conclusions however and prospective for future research Caveolin-3 has been considered to regulate numerous signal pathways for maintaining the normal integrity of skeletal muscles, but the in vivo significance of signal alterations by loss of caveolin-3 in the pathogenesis of LGMD1C/AD-RMD has not been well delineated. As reviewed herein, caveolin-3 regulates myostatin signaling in vitro, and thus disrupted interaction between caveolin-3 and myostatin could contribute to the pathogenesis of caveolin-3-deficient muscular dystrophy (Fig. ​(Fig.11).