Abnormal contractile properties of muscle fibers expressing beta-myosin heavy chain gene mutations in patients with hypertrophic cardiomyopathy.

Abstract

Missense mutations in the 13-myosin heavy chain (, gene cause hypertrophic cardiomyopathy (HCM). As normal and mutant J-MHCs are expressed in slow-twitch skeletal muscle of HCM patients, we compared the contractile properties of single slow-twitch muscle fibers from patients with three distinct 8-MHC gene mutations and normal controls. Fibers with the 741Gly'Arg mutation (near the binding site of essential light chain) demonstrated decreased maximum velocity of shortening (39% of normal) and decreased isometric force generation (42% of normal). Fibers with the 403ArI'n mutation (at the actin interface of myosin)showed lowered force/stiffness ratio (56% of normal) and depressed velocity of shortening (50% of normal). Both the 741Gfr'Ar and 403Ar"9' mutation-containing fibers displayed abnormal force-velocity relationships and reduced power output. Fibers with the 256G1Y"lu mutation (end of ATP-binding pocket) had contractile properties that were indistinguishable from nornal. Thus there is variability in the nature and extent of functional impairments in skeletal fibers containing different fi-MHC gene mutations, which may correlate with the severity and penetrance of the disease that results from each mutation. These functional alterations likely constitute the primary stimulus for the cardiac hypertrophy that is characteristic of this disease. (J. Clin.

Clinical Characteristics of Heart Disease Patients With a Good Prognosis in Spite of Markedly Increased Plasma Levels of Type-B Natriuretic Peptide (BNP)

“…In the present study histological assessment by cardiac biopsy was not performed because the study patients were clinically stable outpatients. Genetic analyses have shown causal mutation of genes encoding cardiac sarcomere proteins, 30 suggesting impaired force production [31][32][33] associated with the inefficient use of adenosine triphosphate (ATP) as the crucial disease mechanism. 32 Therefore, hypertrophy could possibly be a means of compensation for low force generation although precise pathomechanisms have not yet been clarified.…”

Mutations in the motor domain modulate myosin activity and myofibril organization

“…the chicken N118 gene is like the human β-cardiac gene in that it is expressed in both skeletal and cardiac muscle (Cuda et al, 1993;Fananapazir et al, 1993;Lankford et al, 1995).…”

Sarcopenia and its implications for the elderly

“…A handful of studies of the contractile properties and biochemical composition of human single muscle ®ber have been published (Fitts et al, 1989;Larsson & Moss, 1993;Harridge et al, 1995;Lankford et al, 1995;Larsson et al, 1995Larsson et al, , 1996Larsson & Frontera, 1997;Widrick et al, 1996Widrick et al, , 1997Galler et al, 1997). However, as noted above, the cellular mechanisms underlying muscle weakness and atrophy in aging humans have not been elucidated.…”