Caveolin-3, the muscle-specific
isoform of
caveolins, plays important roles in signal transduction. Dominant-negative mutations of the
caveolin-3 gene cause autosomal dominant
limb-girdle muscular dystrophy 1C (
LGMD1C) with loss of
caveolin-3. However, identification of the precise molecular mechanism leading to
muscular atrophy in caveolin-3-deficient muscle has remained elusive.
Myostatin, a member of the muscle-specific
TGF-beta superfamily, negatively regulates skeletal muscle volume. Here we report that
caveolin-3 inhibited
myostatin signaling by suppressing activation of its type I receptor; this was followed by hypophosphorylation of an intracellular effector, Mad homolog 2 (Smad2), and decreased downstream transcriptional activity. Loss of
caveolin-3 in P104L mutant
caveolin-3 transgenic mice caused
muscular atrophy with increase in phosphorylated Smad2 (p-Smad2) as well as p21 (also known as Cdkn1a), a
myostatin target gene. Introduction of the
myostatin prodomain, an inhibitor of
myostatin, by genetic crossing or intraperitoneal administration of the soluble type II
myostatin receptor, another inhibitor, ameliorated
muscular atrophy of the mutant
caveolin-3 transgenic mice with suppression of p-Smad2 and p21 levels. These findings suggest that
caveolin-3 normally suppresses the
myostatin-mediated signal, thereby preventing
muscular atrophy, and that hyperactivation of
myostatin signaling participates in the pathogenesis of
muscular atrophy in a mouse model of
LGMD1C.
Myostatin inhibition may be a promising
therapy for
LGMD1C patients.