Journal Article

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

Coen A.C. Ottenheijm, Michael W. Lawlor, Ger J.M. Stienen, Henk Granzier and Alan H. Beggs

in Human Molecular Genetics

Volume 20, issue 10, pages 2015-2025
Published in print May 2011 | ISSN: 0964-6906
Published online February 2011 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddr084
Changes in cross-bridge cycling underlie muscle weakness in patients with tropomyosin 3-based myopathy

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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.

Journal Article.  7369 words.  Illustrated.

Subjects: Genetics and Genomics

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