Changes in cross-bridge cycling underlie muscle weakness in patients with tropomyosin 3-based myopathy. Hum Mol Genet 2011 May 15;20(10):2015-25
Date
03/02/2011Pubmed ID
21357678Pubmed Central ID
PMC3080611DOI
10.1093/hmg/ddr084Scopus ID
2-s2.0-79955371742 (requires institutional sign-in at Scopus site) 56 CitationsAbstract
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.
Author List
Ottenheijm CA, Lawlor MW, Stienen GJ, Granzier H, Beggs AHAuthor
Michael W. Lawlor MD, PhD Adjunct Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdultCalcium
Child, Preschool
Female
Humans
Infant
Kinetics
Male
Middle Aged
Muscle Contraction
Muscle Fibers, Skeletal
Muscle Weakness
Mutation
Myopathies, Nemaline
Phenotype
Tropomyosin
