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Nemaline myopathy, the most common non-dystrophic congenital myopathy, is caused by mutations in six genes, all of which encode thin-filament proteins, including  NEB  (nebulin) and  TPM3  (α tropomyosin). In contrast to the mechanisms underlying weakness in  NEB -based myopathy, which are related to loss of thin-filament functions normally exerted by nebulin, the pathogenesis of muscle weakness in patients with  TPM3  mutations remains largely unknown. Here, we tested the hypothesis that the contractile phenotype of  TPM3 -based myopathy is different from that of  NEB -based myopathy and that this phenotype is a direct consequence of the loss of the specific functions normally exerted by tropomyosin. To test this hypothesis, we used a multidisciplinary approach, including muscle fiber mechanics and confocal and electron microscopy to characterize the structural and functional phenotype of muscle fibers from five patients with  TPM3 -based myopathy and compared this with that of unaffected control subjects. Our findings demonstrate that patients with  TPM3 -based myopathy display a contractile phenotype that is very distinct from that of patients with  NEB -based myopathy. Whereas both show severe myofilament-based muscle weakness, the contractile dysfunction in  TPM3 -based myopathy is largely explained by changes in cross-bridge cycling kinetics, but not by the dysregulation of sarcomeric thin-filament length that plays a prominent role in  NEB -based myopathy. Interestingly, the loss of force-generating capacity in  TPM3 -based myopathy appears to be compensated by enhanced thin-filament activation. These findings provide a scientific basis for differential therapeutics aimed at restoring contractile performance in patients with  TPM3 -based versus  NEB -based myopathy.

Changes in cross-bridge cycling underlie muscle weakness in patients with tropomyosin 3-based myopathy