De. Michele et Jm. Metzger, Physiological consequences of tropomyosin mutations associated with cardiac and skeletal myopathies, J MOL MED-J, 78(10), 2000, pp. 543-553
Citations number
83
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Medical Research General Topics
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 contr
actile function of fully differentiated striated muscle cells. Both FHC and
NM mutant alpha -Tm proteins incorporated normally into the adult muscle s
arcomere, 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+-ac
tivated force production that may underlie, at least in part, the muscle we
akness observed in NM. Taken together, the results suggest that the differe
ntial changes in the ability of the mutant Tm proteins to regulate muscle c
ontraction in response to changing Ca2+ concentrations underlie the differe
ntial clinical presentation of the cardiac and skeletal muscle myopathies a
ssociated with mutations in alpha -Tm.