Who can better resist the adverse effects of disuse on muscles: men or women?

Abstract

Changes in lifestyle due to health problems or personal events, confinement to bed following a disease or immobilization with a limb in a cast are frequent causes of severe reduction in physical activity. The persistent disuse is followed by an adaptive response of skeletal muscle, the hallmarks of which are reductions in muscle mass and in strength (for a recent review see Blaauw et al. 2013). The decline in muscle mass is accompanied by a proportional reduction in muscle power and an even greater reduction in muscle strength, pointing to a reduction of normalized force. Atrophy, i.e. decrease in cross-sectional area, decrease in force and decrease in power output are also detectable in single muscle fibres and are more pronounced in slow than in fast fibres. A slow-to-fast transition, with a reduction in the proportion of slow fibres and an increased proportion of hybrid fibres, is also detectable. The loss of muscle mass and the decrease in muscle fibre cross-sectional area are determined by a predominance of protein degradation over protein synthesis. The two major catabolic systems, ubiquitin–proteasome and autophagy, are both activated, while simultaneously, the rate of protein synthesis is also reduced. An alteration in redox homeostasis is generally accepted to contribute significantly to the mechanisms of atrophy. Importantly, contractile impairment and atrophy are accompanied by an alteration in energy metabolism, involving both oxidative and glycolytic pathways, with mitochondrial dysfunction playing a primary role. After only a few days of complete inactivity, for example in bed rest experiments, insulin resistance increases, thus confirming the impact of muscle inactivity on metabolism. Due to the high plasticity of skeletal muscles, all or most signs of this adaptation to disuse are reversible when activity is resumed. After an adequate period of rehabilitation, muscles can recover their structural, contractile and metabolic characteristics. The adaptive response to disuse of skeletal muscle becomes particularly relevant in the elderly. For example, when the loss of muscle mass due to disuse is added to that related to ageing, the atrophic response becomes even more pronounced. Reversibility, on the other hand, is reduced; a period of disuse can cause irreversible decline in muscle mass and function, possibly leading to loss of independent life and severe metabolic alterations. An aspect of the response to disuse and, in particular, of disuse in the elderly that is worthy of consideration is the differential response between males and females. Epidemiological studies in the elderly (for example, the Framingham study, as discussed by Dufour et al. 2013) have shown that the disability rate is higher in women than in men above 65 years old. Several factors can contribute to this, including lifestyle and long-lasting impairment of the locomotion system (bones, joints and muscles), partly triggered by the sudden hormonal decline associated with menopause. However, there might be a further, more severe and more specific impact of reduced activity in women. The paper by Callahan and coworkers (2014) provides a significant contribution to this issue. A model of long-lasting (several years) and moderate reduction of activity due to knee osteoarthritis was studied as an alternative to the most popular models of more complete but less prolonged inactivity (from a few weeks to 3 months) obtained with bed rest or unilateral limb suspension. The comparison between control and inactive subjects and between males and females was carried out at all levels from body composition to leg extensor muscle performance, from single muscle fibre mechanics to cross-bridge and myosin post-translational modification. The emerging picture points to a greater loss in power output of muscle fibres in females. Data show that such greater contractile impairment is explained by the lack in females of a specific adaptive component, i.e. the increase in shortening velocity which, in males, parallels the decrease in isometric force, leading to a maintained power output. The increase in shortening velocity is paralleled, at the cross-bridge level, by the reduction in the parameter ton, the average attachment time of myosin to actin. Callahan and coworkers (2014) offer an explanation of why muscle fibres in women lack this compensatory mechanism. They suggest that oxidative stress acts on contractile proteins, and does so more in women than in men. It is noteworthy that the increase in shortening velocity, which was first reported in bed rest and microgravity studies in healthy young adult subjects, was recently confirmed (Reid et al. 2014) in a longitudinal study in the elderly with motor impairment. However, no change in shortening velocity was observed in muscle fibres of women at end of 2 months of bed rest (Trappe et al. 2007). As rightfully discussed by the authors, several aspects of this male–female comparison need further investigation. Key among these is the impact of hormonal status, taking into account that in the age range (65–75 years) examined by Callahan et al. (2014), women have been in the postmenopausal condition for many years, while men are experiencing a more gradual and progressive decay of their hormonal levels. Neurological components should also be considered. Little is known about the possible diversity between males and females in the ageing-related motor neuron loss and muscle fibre denervation process. As expected, any new finding opens the way to new investigations and, in this case, with possible relevance for the health and quality of life of the elderly.