Targeting the type I TGF-β receptor for treating caveolin-3-deficient autosomal dominant limb-girdle muscular dystrophy type 1C and muscle wasting disorders

Abstract

Caveolin-3, the principal scaffold protein in sarcolemmal caveolae, regulates signal transduction and vesicular trafficking. Dominant-negative mutations in the caveolin-3 gene (CAV3) cause autosomal dominant limb-girdle muscular dystrophy 1C (LGMD1C) and autosomal dominant rippling muscle disease (AD-RMD). Myostatin, a member of the muscle-specific transforming growth factor (TGF)-β family, negatively regulates muscle growth and volume. We recently showed that wild-type caveolin-3 binds to and inhibits TGF-β type I receptor (TβRI), thereby suppressing intracellular TGF-β signaling. In contrast, LGMD1C-causing mutant caveolin-3 activates TβRI, resulting in muscle atrophy. Recently, small-molecule compounds suppressing activation of TβRI, also known as activin receptor-like kinase 5 (ALK5), have been developed as anticancer agents. Oral administration of a TβRI inhibitor, Ki26894, ameliorates muscle atrophy and weakness in a caveolin-3-deficient LGMD1C mouse model. The therapeutic effect of Ki26894 is associated with a reduction in TGF-β signaling and an increase in the number of muscle precursor satellite cells. This suggests that the caveolin-3/TβRI signaling pathway plays an important role in the pathogenesis of LGMD1C and that it regulates skeletal muscle size by controlling the number of muscle precursor cells. Consequently, drugs that target the TGF-β pathway may have therapeutic potential for diseases characterized by muscle atrophy.