Myosin Heavy Chain Isoform Expression in the Failing and Nonfailing Human Heart

Abstract

Abstract-In the heart, the relative proportions of the 2 forms of the motor protein myosin heavy chain (MyHC) have been shown to be affected by a wide variety of pathological and physiological stimuli. Hearts that express the faster MyHC motor protein, ␣, produce more power than those expressing the slower MyHC motor protein, ␤, leading to the hypothesis that MyHC isoforms play a major role in the determination of cardiac contractility. We showed previously that a significant amount of ␣MyHC mRNA is expressed in nonfailing human ventricular myocardium and that ␣MyHC mRNA expression is decreased 15-fold in end-stage failing left ventricles. In the present study, we determined the MyHC protein isoform content of human heart samples of known MyHC mRNA composition. We demonstrate that ␣MyHC protein was easily detectable in 12 nonfailing hearts.

Low-intensity exercise training delays onset of decompensated heart failure in spontaneously hypertensive heart failure rats

“…However, Tardiff et al (65) found a 15% decrease in cardiac contractility in a transgenic mouse model overexpressing ␤-MyHC, whereas another study (23) showed decreased power output in skinned cardiac myocytes overexpressing ␤-MyHC. It is generally thought that a greater percentage of ␣-MyHC protein is associated with a healthier state of the myocardium in rats and possibly in humans (35). In the current study, we found a significantly higher expression of ␣-MyHC protein in the exercise-trained animals at all ages.…”

Factors controlling cardiac myosin-isoform shift during hypertrophy and heart failure

“…αMHC, whereas the opposite is true of animals with a sedentary life style [19]. In the adult human heart, αMHC has been detected at about 30% of the total MHC mRNA and 10-12% of the total myosin protein [7]. A recent study, however, suggests that αMHC may be as high as 70% of the total myosin pool in human neonates, and that this gradually decreases with age [20].…”

“…In animal models of pressure overload, such as aortic constriction in rats, mice and rabbits, the relative proportion of αMHC has been shown to decrease during pathologic hypertrophy, but it was never found to be completely eliminated [104][105][106][107]. In human failing hearts the αMHC isoform, which is nearly 10% of the total MHC pool, decreased to nearly non-detectable levels, and this was suggested to be a critical determinant of transition of the heart from adaptive hypertrophy to failure [7,9]. This idea is supported by experiments in which blocking of the MHC isoform shift by thyroid-hormone intervention prevented the functional decompensation of the heart in an aortic-banding model of heart failure [108].…”

“…Examination of different biophysical and biochemical parameters has revealed that a shift in the myosin-isoform distribution and a change in the cross bridge cycling characteristics of the sarcomere play a significant role in controlling the shortening velocity of cardiac muscle fibers [2][3][4]. With recent evidence confirming the presence of αMHC in human hearts and its disappearance in failing hearts, a new interest has arisen among investigators in finding ways of restoring and/or up-regulating the αMHC expression in the overloaded heart [5][6][7][8]. The basic premise is that reduction of cardiac hypertrophy combined with increased activity of αMHC could be beneficial in terms of increasing the myocardial contractility of a hemodynamically challenged heart [9].…”

Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip

“…Over time, remodeling transitions from adaptive to maladaptive, which is characterized structurally by sarcomere disarray (4), fibrosis (5), myocyte elongation (2,6,7), and ventricular dilation (3). Gene expression reverts to an immature state, including down-regulation of α-myosin heavy chain (MHC) concurrent with up-regulation of β-MHC, reminiscent of the relative expression levels of these motor proteins in the embryonic heart (8,9). Functionally, myocytes isolated from failing hearts show defective excitationcontraction coupling (10), including reduced calcium uptake into the sarcoplasmic reticulum (11).…”