A nemaline myopathy mutation in α-tropomyosin causes defective regulation of striated muscle force production

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Abstract

Nemaline myopathy (NM) is a rare autosomal dominant skeletal muscle myopathy characterized by severe muscle weakness and the subsequent appearance of nemaline rods within the muscle fibers. Recently, a missense mutation inTPM3, which encodes the slow skeletal α-tropomyosin (αTm), was linked to NM in a large kindred with an autosomal-dominant, childhood-onset form of the disease. We used adenoviral gene transfer to fully differentiated rat adult myocytes in vitro to determine the effects of NM mutant human αTm expression on striated muscle sarcomeric structure and contractile function. The mutant αTm was expressed and incorporated correctly into sarcomeres of adult muscle cells. The primary defect caused by expression of the mutant αTm was a decrease in the sensitivity of contraction to activating Ca2+, which could help explain the hypotonia seen in NM. Interestingly, NM mutant αTm expression did not directly result in nemaline rod formation, which suggests that rod formation is secondary to contractile dysfunction and that load-dependent processes are likely involved in nemaline rod formation in vivo.

Authors

Daniel E. Michele, Faris P. Albayya, Joseph M. Metzger