An αtropomyosin mutation alters dimer preference in nemaline myopathy

Abstract

Nemaline myopathy is a human neuromuscular disorder associated with muscle weakness, Z-line accumulations (rods), and myofibrillar disorganization. Disease-causing mutations have been identified in genes encoding muscle thin filament proteins: actin, nebulin, slow troponin T, βTropomyosin, and αTropomyosinslow. Skeletal muscle expresses three tropomyosin (Tm) isoforms from separate genes: αTmfast(αTm, TPM1), βTm (TPM2), and αTmslow (γTm, TPM3). In this article, we show that the level of βTm, but not αTmfast protein, is reduced in human patients with mutations in αTmslow and in a transgenic mouse model of αTmslow(Met9Arg) nemaline myopathy. A postnatal time course of Tm expression in muscles of the mice indicated that the onset of αTmslow(Met9Arg) expression coincides with the decline of βTm. Reduction of βTm levels is independent of the degree of pathology (rods) within a muscle and is detected before the onset of muscle weakness. Thus, reduction in the level of βTm represents an early clinical diagnostic marker for aTmslow-based mutations. Examinations of tropomyosin dimer formation using either recombinant proteins or sarcomeric extracts show that the mutation reduces the formation of the preferred α/β heterodimer. We suggest this perturbation of tropomyosin isoform levels and dimer preference alters sarcomeric thin filament dynamics and contributes to muscle weakness in nemaline myopathy.