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

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 Ca(2+) 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 (k(tr)) were assessed in solutions with varying Ca(2+) concentrations (pCa), allowing construction of relative force-pCa and k(tr)-pCa relationships. Results showed a rightward shift of the relative force-pCa relationship and a leftward shift of the relative k(tr)-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 k(tr) were predominantly due to a decrease in the relative number of attached cross-bridges at different pCa values. Thus, a change in Ca(2+) 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.