Key pointsr Muscle disuse that accompanies ageing and chronic disease may hasten physical disability by impairing skeletal muscle contractility.r We compared skeletal muscle contractile function at the various anatomic levels between two groups of older men and women matched for sex, health status and body size, of which one group was habitually active and the other inactive.r Muscle disuse reduced force generation, power output and contractile velocity in single muscle fibres, with differential adaptations in some parameters in men and women. Sex-specific cellular phenotypes were explained by differential adaptations in molecular muscle function. Moreover, aspects of the molecular functional phenotype apparent in inactive women could be recapitulated in vitro by chemical modification of protein thiols.r Our results identify molecular and cellular contractile dysfunction in skeletal muscle that may contribute to reduced physical function with muscle disuse, with sex-specific differences that may explain a greater disposition towards disability in women.Abstract Physical inactivity that accompanies ageing and disease may hasten disability by reducing skeletal muscle contractility. To characterize skeletal muscle functional adaptations to muscle disuse, we compared contractile performance at the molecular, cellular and whole-muscle levels in healthy active older men and women (n = 15) and inactive older men and women with advanced-stage, symptomatic knee osteoarthritis (OA) (n = 16). OA patients showed reduced (P < 0.01) knee extensor function. At the cellular level, single muscle fibre force production was reduced in OA patients in myosin heavy chain (MHC) I and IIA fibres (both P < 0.05) and differences in IIA fibres persisted after adjustments for fibre cross-sectional area (P < 0.05). Although no group differences in contractile velocity or power output were found for any fibre type, sex was found to modify the effect of OA, with a reduction in MHC IIA power output and a trend towards reduced shortening velocity in women, but increases in both variables in men (P < 0.05 and P = 0.07, respectively). At the molecular level, these adaptations in MHC IIA fibre function were explained by sex-specific differences (P ࣘ 0.05) in myosin-actin cross-bridge kinetics. Additionally, cross-bridge kinetics were slowed in MHC I fibres in OA patients (P < 0.01), attributable entirely to reductions in women with knee OA (P < 0.05), a phenotype that could be reproduced in vitro by chemical modification of protein thiol residues. Our results identify molecular and cellular functional adaptations in skeletal muscle that may contribute to reduced physical function with knee OA-associated muscle disuse, with sex-specific differences that may explain a greater disposition towards disability in women. Abbreviations A, A-process magnitude; B, B-process magnitude; BMI, body mass index; C, C-process magnitude; CP, creatine phosphate; CPK, creatine phosphokinase; CSA, cross-sectional area; DTT, dithiothreitol; f, frequency of length pertu...

Many patients with cancer experience physical disability following diagnosis, although little is known about the mechanisms underlying these functional deficits. To characterize skeletal muscle adaptations to cancer in humans, we evaluated skeletal muscle structure and contractile function at the molecular, cellular, whole-muscle, and whole-body level in 11 patients with cancer (5 cachectic, 6 noncachectic) and 6 controls without disease. Patients with cancer showed a 25% reduction in knee extensor isometric torque after adjustment for muscle mass (P < 0.05), which was strongly related to diminished power output during a walking endurance test (r = 0.889; P < 0.01). At the cellular level, single fiber isometric tension was reduced in myosin heavy chain (MHC) IIA fibers (P = 0.05) in patients with cancer, which was explained by a reduction (P < 0.05) in the number of strongly bound cross-bridges. In MHC I fibers, myosin-actin cross-bridge kinetics were reduced in patients, as evidenced by an increase in myosin attachment time (P < 0.01); and reductions in another kinetic parameter, myosin rate of force production, predicted reduced knee extensor isometric torque (r = 0.689; P < 0.05). Patients with cancer also exhibited reduced mitochondrial density (-50%; P < 0.001), which was related to increased myosin attachment time in MHC I fibers (r = -0.754; P < 0.01). Finally, no group differences in myofilament protein content or ultrastructure were noted that explained the observed functional alterations. Collectively, our results suggest reductions in myofilament protein function as a potential molecular mechanism contributing to muscle weakness and physical disability in human cancer.