Effects of a preferential myosin loss on Ca2+ activation of force generation in single human skeletal muscle fibres

Abstract

Preferential loss of the motor protein myosin, as observed in patients with acute quadriplegic myopathy (AQM) or cancer cachexia, causes generalized muscle wasting, muscle weakness and a decrease in muscle fibre force normalized to cross-sectional area. It remains unclear, however, whether this myosin loss influences other important features of muscle fibre function, such as Ca 2+ activation of the contractile proteins. To address this question, we have studied Ca2+ sensitivity of force generation using skinned muscle fibres from four patients with AQM or cancer cachexia and a preferential loss of myosin; and from seven healthy control individuals. Force and apparent rate constant of force redevelopment (ktr) were assessed in solutions with varying Ca2+ concentrations (pCa), allowing construction of relative force-pCa and ktr-pCa relationships. Results showed a rightward shift of the relative force-pCa relationship and a leftward shift of the relative ktr-pCa curve in muscle fibres with a preferential myosin loss. To improve the understanding of the mechanisms underlying these alterations, the relative stiffness-pCa relationship was evaluated. A rightward shift of this curve was observed, suggesting that the changes in the Ca 2+ activation of force and ktr were predominantly due to a decrease in the relative number of attached cross-bridges at different pCa values. Thus, a change in Ca2+ activation of the contractile apparatus in patients with preferential myosin loss is proposed as an additional factor contributing to the muscle function impairment in these patients. © 2008 The Authors.