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

• Published in: Human molecular genetics Vol. 20; no. 10; pp. 2015 - 2025
• Main Authors: Ottenheijm, C. A. C., Lawlor, M. W., Stienen, G. J. M., Granzier, H., Beggs, A. H.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.05.2011
• Subjects: Adult; Biological and medical sciences; Calcium - metabolism; Child, Preschool; Electron microscopy; Female; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Humans; Infant; Kinetics; Male; Middle Aged; Molecular and cellular biology; Muscle Contraction; Muscle Fibers, Skeletal - pathology; Muscle Weakness - genetics; Muscle Weakness - pathology; Muscles; Mutation; Mutation - genetics; Myopathies, Nemaline - genetics; Myopathies, Nemaline - pathology; Myopathy; Nemaline myopathy; Phenotype; Structure-function relationships; Tropomyosin; Tropomyosin - genetics; Tropomyosin - metabolism; Human; Genetics; Muscle; Tropomyosin 3; Myopathy
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddr084

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.