The effect of gender and obesity in modulating cross-bridge function in cardiac muscle fibers.

Abstract

The effect of obesity on cross-bridge (CB) function was investigated in mice lacking functional Melanocortin-4 Receptor (MC4R^-/-), the loss of which causes dilated cardiomyopathy (DCM) in humans and mice. Skinned cardiac muscle fibers from male and female mice were used, and activated in the presence of Ca²⁺. To characterize CB kinetics, we changed the length of fibers in sinewaves (15 frequencies: 1‒187 Hz) at a small amplitude (0.2%L₀), studied concomitant tension transients, and deduced the kinetic constants of the CB cycle from the ATP and Pi effects. In males, active tension and stiffness during full activation and rigor were ~ 1.5X in WT compared to MC4R^-/- mice. This effect was not observed in females. We also observed that ATP binding and subsequent CB detachment steps were not altered by the mutation/gender. The equilibrium constant of the force generation step (K₄) and Pi release step (association constant: K₅) were not affected by the mutation, but there was a gender difference in WT mice: K₄ and K₅ were ~ 2.2X in males than in females. Concomitantly, the forward rate constant (r₄) and backward rate constant (r_-4) of the force generation step were 1.5-2.5X in muscles from female MC4R^-/- mice relative to male MC4R^-/- mice. However, these effects did not cause a significant difference in CB distributions among six CB states. In both genders, Ca²⁺ sensitivity decreased slightly (0.12 pCa unit) in mutants. We conclude that the CB functions are differentially affected both by obesity induced in the absence of functional MC4R^-/- and gender.