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

Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip

“…Heart failure is associated with increased expression of the slow MHC isoform β-MHC relative to the expression of the fast MHC isoform α-MHC, conserving energy but reducing contractility in rodents (8). We used RT-PCR to determine the ratio of α-/β-MHC mRNA at 96 h and found that this ratio was lowest for all stretched tissues (Fig.…”

“…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).…”

Histone Deacetylase 3 (HDAC3)-dependent Reversible Lysine Acetylation of Cardiac Myosin Heavy Chain Isoforms Modulates Their Enzymatic and Motor Activity

“…The ␣-MHC isoform has higher ATPase activity and accounts for a faster rate of actin-sliding velocity than the ␤-MHC isoform with low ATPase activity. The relative distribution of the two cardiac MHC isoforms is regulated developmentally and by various pathophysiological stimuli (11). In young adult rodents, the ␣-to ␤-MHC isoform ratio is nearly 95:5, which changes with growth and age of the heart (11).…”

“…During exercise-induced physiologic hypertrophy, there is no significant change in MHC isoform distribution, whereas during pathologic hypertrophy, ␤-MHC levels are elevated at the expense of the ␣-MHC isoform. This MHC isoform shift plays a major role in regulating the contractile function of the hearts of rodents (11). However, the functional significance of MHC isoform shift in large mammals is controversial because they express mainly one isoform, ␤-MHC (12).…”

Negative Regulation of the Thyrotropin β Gene by Thyroid Hormone

“…This is supported by an in vivo study, which showed that the overexpression of these co-repressors is incompatible with physiological regulation of TRH (Becker et al, 2001). As in the cases of the TSH and GSU genes, mRNA expression of the myosin heavy chain subunit (MHC ) gene in the heart is also repressed by T3/TR (Gupta, 2007). In NCoRΔID mice, T3-induced inhibition of MHC is maintained (Astapova et al, 2011).…”