title: Changes in cross-bridge cycling underlie muscle weakness in patients with tropomyosin 3-based myopathy.
abstract: 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.
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam 1081 BT, The Netherlands. c.ottenheijm@vumc.nl
authors.forename: Coen A C
authors.initials: CA
authors.lastname: Ottenheijm
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lawlor
authors.forename: Ger J M
authors.initials: GJ
authors.lastname: Stienen
authors.forename: Henk
authors.initials: H
authors.lastname: Granzier
authors.forename: Alan H
authors.initials: AH
authors.lastname: Beggs
mesh_terms: D000328:Adult; D002118:Calcium / Q000378:metabolism; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D018908:Muscle Weakness / Q000235:genetics / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D017696:Myopathies, Nemaline / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype; D014335:Tropomyosin / Q000235:genetics* / Q000378:metabolism*
chemical_list: D014335:Tropomyosin; D002118:Calcium