Role of myosin heavy chain composition in kinetics of force development and relaxation in rat myocardium

Abstract

The effects of ventricular myosin heavy chain (MHC) composition on the kinetics of activation and relaxation were examined in both chemically skinned and intact myocardial preparations from adult rats. Thyroid deficiency was induced to alter ventricular MHC isoform expression from ∼80 %α‐MHC/20 %β‐MHC in euthyroid rats to 100 %β‐MHC, without altering the expression of thin‐filament‐associated regulatory proteins. In single skinned myocytes, increased expression of β‐MHC did not significantly affect either maximal Ca2+‐activated tension (P0) or the Ca2+ sensitivity of tension (pCa50). However, unloaded shortening velocity (V0) decreased by 80 % due to increased β‐MHC expression. The kinetics of activation and relaxation were examined in skinned multicellular preparations using the caged Ca2+ compound DM‐nitrophen and caged Ca2+ chelator diazo‐2, respectively. Myocardium expressing 100 %β‐MHC exhibited apparent rates of submaximal and maximal tension development (kCa) that were 60 % lower than in control myocardium, and a 2‐fold increase in the half‐time for relaxation from steady‐state submaximal force. The time courses of cell shortening and intracellular Ca2+ transients were assessed in living, electrically paced myocytes, both with and without β‐adrenergic stimulation (70 nm isoproterenol (isoprenaline)). Thyroid deficiency had no affect on either the extent of myocyte shortening or the resting or peak fura‐2 fluorescence ratios. However, induction of β‐MHC expression by thyroid deficiency was associated with increased half‐times for myocyte shortening and relengthening and increased half‐time for the decay of the fura‐2 fluorescence ratio. Qualitatively similar results were obtained in both the absence and the presence of β‐adrenergic stimulation although the β‐agonist accelerated the kinetics of the twitch and the Ca2+ transient. Collectively, these data provide evidence that increased β‐MHC expression contributes significantly to the observed depression of contractile function in thyroid deficient myocardium by slowing the rates of both force development and force relaxation.

Effects of a myofilament calcium sensitizer on left ventricular systolic and diastolic function in rats with volume overload heart failure

“…Historically, the rate of cross-bridge detachment was thought to be rate limiting because it was significantly slower than the rate of Ca 2ϩ dissociation from TnC (11,23). However, newer data suggest that the rate of cross-bridge detachment is temperature sensitive, and, at near physiological temperatures, the rate of cross-bridge detachment is faster than the rate of Ca 2ϩ dissociation from TnC, suggesting that Ca 2ϩ is rate limiting (23).…”

“…cTnI regulates thin-filament function, and Ser-23/24 phosphorylation by PKA decreases Ca 2ϩ sensitivity and myofilament cross-bridge cycling kinetics (31,36) and increases the rate of cTnC-Ca 2ϩ dissociation (23). Finally, chemically skinned myocardium containing primarily ␣-MHC has a higher ATPase rate, faster sarcomeric shortening velocity, faster rate of tension relaxation, higher power production, and greater rate of force development compared with ␤-MHC (11,39). Taken together, we suggest that there is a complex interrelationship among these three proteins, and the relative importance of each in our model depends on hemodynamic load as well as presence or absence of the myofilament Ca 2ϩ sensitizer.…”

“…According to Fitzsimmons et al (11), tension relaxation is governed by several interrelated factors, including the rate of cross-bridge detachment, reattachment of previously detached cross-bridges, and calcium dissociation from TnC. Historically, the rate of cross-bridge detachment was thought to be rate limiting because it was significantly slower than the rate of Ca 2ϩ dissociation from TnC (11,23).…”

Designing Heart Performance by Gene Transfer

“…Most studies that have examined the effect of myosin isoform switching on cardiac muscle function have used hyper-or hypothyroid animals (235,356) and transgenic mice (455,873) or rabbits (401). It is difficult to determine the direct effect of myosin isoform shifts in these models because the phenotype represents the combined effects of myosin isoform and the compensatory response to the hormonal or genetic manipulation.…”

“…For example, ␤-MyHC, the "slow" molecular motor, hydrolyzes ATP three to seven times slower than ␣-MyHC (330, 918). The "fast" motor, ␣-MyHC, represents Ͼ90% of the total myosin expressed in the normal adult rodent heart (235,356,553). Expression of the slow ␤-MyHC motor increases relative to ␣-MyHC in rodent models of cardiovascular disease including diabetes (762), hypothyroidism, cardiac hypertrophy (553), and aging (99,236,932).…”