Caveolin-3 regulates myostatin signaling. Mini-review

Abstract

Caveolins, components of the uncoated invaginations of plasma membrane, regulate signal transduction and vesicular trafflicking. Loss of caveolin-3, resulting from dominant negative mutations of caveolin-3 causes autosomal dominant limb-girdle muscular dystrophy (LGMD) 1C and autosomal dominant rippling muscle disease (AD-RMD). Myostatin, a member of the muscle-specific transforming growth factor (TGF)-beta superfamily, negatively regulates skeletal muscle volume. Herein we review caveolin-3 suppressing of activation of type I myostatin receptor, thereby inhibiting subsequent intracellular signaling. In addition, a mouse model of LGMD1C has shown atrophic myopathy with enhanced myostatin signaling. Myostatin inhibition ameliorates muscular phenotype in the model mouse, accompanied by normalized myostatin signaling. Enhanced myostatin signaling by caveolin-3 mutation in human may contribute to the pathogenesis of LGMD1C. Therefore, myostatin inhibition therapy may be a promising treatment for patients with LGMD1C. More recent studies concerning regulation of TGF-beta superfamily signaling by caveolins have provided new insights into the pathogenesis of several human diseases.

Figure 1

Putative scheme of the regulation of myostatin signaling by caveolin-3. Myostatin (MSTN) signaling is propagated through the myostatin receptor, a heteromeric complex consisting with transmembrane receptor serine/threonine kinases. Myostatin binds to and phosphorylates its type II serine/threonine kinase receptor (Type II Receptor). Subsequently, its type I serine/threonine kinase receptor (Type I Receptor) is phosphorylated by Type II Receptor and is recruited into the heteromeric complex, which in turn phosphorylates receptor-regulated Smads (R-Smads), a family of transcription factor controlling the expression of specific target genes. Caveolin-3 (CAV-3) binds to and suppresses activation of the Type I Receptor of MSTN at the plasma membrane and suppresses intracellular myostatin signaling, including phosphorylation of R-Smads and transcription of specific target genes. Loss of caveolin-3 resulting from dominant negative mutations of the caveolin-3 genes in patients with LGMD1C could enhance intracellular myostatin signaling, and thereby result in muscle mass reduction. Type II Receptor, ActRIIB; Type I Receptor, ALK4/5; R-Smads, Smad2/3. P indicates phosphorylation.