Physiological consequences of tropomyosin mutations associated with cardiac and skeletal myopathies.
Mutations have been identified in alpha-tropomyosin (Tm), a key regulatory protein in striated muscle cells, that are associated with a human cardiac myopathy, hypertrophic cardiomyopathy (FHC) and a human skeletal myopathy, nemaline myopathy (NM). In this review, we highlight experiments aimed at identifying the underlying mechanisms by which mutations in alpha-Tm cause inherited diseases of cardiac and skeletal muscle. Gene transfer of normal and mutant alpha-Tm to isolated adult cardiac myocytes was used to study the primary effects of mutant alpha-Tm proteins on the structure and contractile function of fully differentiated striated muscle cells. Both FHC and NM mutant alpha-Tm proteins incorporated normally into the adult muscle sarcomere, similar to normal Tm but exerted differential "dominant-negative" effects on the contractile function of the muscle cell. FHC mutant alpha-Tm proteins produced hypersensitivity of Ca2+-activated force production with a hierarchy that was related to the clinical severity of each mutation. Conversely, the NM mutant alpha-Tm produced a hyposensitivity of Ca2+-activated force production that may underlie, at least in part, the muscle weakness observed in NM. Taken together, the results suggest that the differential changes in the ability of the mutant Tm proteins to regulate muscle contraction in response to changing Ca2+ concentrations underlie the differential clinical presentation of the cardiac and skeletal muscle myopathies associated with mutations in alpha-Tm.
Michele
D E
DE
Department of Physiology, University of Michigan, Ann Arbor 48109, USA.
Metzger
J M
JM
D000595:Amino Acid Sequence; D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009200:Myocardial Contraction; D017696:Myopathies, Nemaline / Q000235:genetics / Q000503:physiopathology*; D014335:Tropomyosin / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*
D014335:Tropomyosin