Role of myosin heavy chain composition in the stretch activation response of rat myocardium

Abstract

The speed and force of myocardial contraction during systolic ejection is largely dependent on the intrinsic contractile properties of cardiac myocytes. As the myosin heavy chain (MHC) isoform of cardiac muscle is an important determinant of the contractile properties of individual myocytes, we studied the effects of altered MHC isoform expression in rat myocardium on the mechanical properties of skinned ventricular preparations. Skinned myocardium from thyroidectomized rats expressing only the β MHC isoform displayed rates of force redevelopment that were about 2.5-fold slower than in myocardium from hyperthyroid rats expressing only the α MHC isoform, but the amount of force generated at a given level of Ca 2+ activation was not different. Because recent studies suggest that the stretch activation response in myocardium has an important role in systolic function, we also examined the effect of MHC isoform expression on the stretch activation response by applying a rapid stretch (1% of muscle length) to an otherwise isometrically contracting muscle fibre. Sudden stretch of myocardium resulted in a concomitant increase in force that quickly decayed to a minimum and was followed by a delayed redevelopment of force (i.e. stretch activation) to levels greater than prestretch force. β MHC expression dramatically slowed the overall rate of the stretch activation response compared to expression of α MHC isoform; specifically, the rate of force decay was ∼2-fold slower and the rate of delayed force development was ∼2.5-fold slower. In contrast, MHC isoform had no effect on the amplitude of the stretch activation response. Collectively, these data show that expression of β MHC in myocardium dramatically slows rates of cross-bridge recruitment and detachment which would be expected to decrease power output and contribute to depressed systolic function in end-stage heart failure.

Determination of rate constants for turnover of myosin isoforms in rat myocardium: implications for in vivo contractile kinetics

“…Altered MHC composition had no effect on the Ca 2ϩ sensitivity of force, and the steepness of the force-pCa relationship (n H ) did not vary between the preparations, indicating that MHC composition does not influence the apparent cooperativity of tension development. Our findings did reveal that maximum Ca 2ϩ -activated force (pCa 4.5) was reduced in preparations expressing 100% ␤-MHC (Table 1), which differs from previous reports (12,20,41,43) showing that maximum force did not change with the expression of MHC isoforms. However, measurements of maximal force per cross-sectional area in enzymatically digested skinned single myocytes from hypothyroid and hyperthyroid rat myocardium revealed no differences (6.5 Ϯ 1.0 and 7.4 Ϯ 0.7 kN/m 2 , respectively).…”

“…These results suggest that the depressed force in the trabeculae of hypothyroid rats may be due to changes in the expression of extracellular elements such as collagen, which has been shown to be increased in rats treated with PTU (49). Alterations of force due to increased collagen would not have been evident in homogenized preparations obtained via mechanical disruption, as in previous reports (12,20,41,43).…”

“…After a brief period (10 ms) of unloaded isotonic shortening, the preparation was rapidly restretched to its original length and force redeveloped to the original steady-state level. The apparent k tr was estimated by linear transformation of the half-time of force redevelopment (t1/2), i.e., ktr ϭ 0.693/t1/2, as previously described (43).…”

Increase in cardiac myosin heavy-chain (MyHC) alpha protein isoform in hibernating ground squirrels, with echocardiographic visualization of ventricular wall hypertrophy and prolonged contraction.

“…These motor proteins differ in their parameters of velocity and force produced (Alpert et al, 2002;Galler et al, 2002;Stelzer et al, 2007); cardiac alpha (α) and beta (β) MyHC isoforms can be differentially expressed by heart chamber, as well as by mass and age of the individual (Dool et al, 1995;Miyata et al, 2000;Barrows et al, 2011). The myocardium is plastic, similar to skeletal muscle, and mechanical loading and other factors can shift the relative isoform abundance of the cardiac motor proteins.…”

“…This may represent an energy-and oxygen-saving mechanism at the expense of force production and peak power (Litten et al, 1982; Litten et al, 1985; Hasenfuss et al, 1991; Herron and McDonald, 2002; Korte et al, 2005). The lower power in turn contributes to depressed systolic function in end-stage heart failure (Stelzer et al, 2007). While MyHC-α decreases in failing hearts, it increases with recovery (Haworth, 2007), and may be cardioprotective in stressed myocardium (Marian, 2005).…”