A protective role for exercise in the age-related loss of muscle mass

Sarcopenia, the age-related loss of muscle mass and function is an impending health issue for the vast majority of people as they reach their sixties and this decline progressively reduces life quality for the affected individual. This is because sarcopenia selectively affects lower limb muscles, which leads to reduced mobility and independence of the elderly individual. The loss of muscle mass is thought to be driven predominantly by denervation-atrophy and loss of individual muscle fibres, which leads to a 40% reduction in total lean mass as well as a decline in muscle strength by the end of the 8th decade of life. The decline in mobility is associated with muscle disuse, which further exacerbates the progression of sarcopenia. Although major efforts have gone into improving our understanding of the cause for age- related fibre atrophy and loss, the underlying mechanisms as well as the relative contributions of fibre atrophy and fibre loss remain poorly understood. Sarcopenia represents a major health problem not only for the affected individual but also for the health care system, as the proportion of the population over the age of sixty-five is projected to increase to 31% by the year 2061. This means a sharp increase in the number of people affected by sarcopenia causing an increased burden on the rest of society. The only trialed and tested intervention to effectively delay sarcopenia is physical exercise, which has been shown to prevent age-related denervation and thus maintain fibre size. In contrast, the sedentary lifestyle adopted by many elderly people has been shown to account for at least some of the muscle loss reported, strongly implicating a role for physical activity in the prevention of sarcopenia. However the specific impact of implementation of endurance exercise regimens in old age on fibre atrophy and fibre loss in lower-limb muscles is still unknown. This study sought to investigate the protective role of endurance exercise in age-related loss of muscle mass, using a well-established mouse model of muscle ageing. In addition, this study sought to examine the mechanism behind age-related fibre loss. Young (4-6 months) and old (24 months) C57BL/6 mice were used to determine the level of denervation, fibre atrophy and fibre loss in lower limb muscles with age. The same parameters were considered for three separate cohorts of young and old mice, assigned to either of two endurance exercise protocols consisting of two or four months of voluntary running or assigned to a two month reduced activity protocol in which wheel running and cage-climbing were prevented. Soleus, extensor digitorum longus (EDL), tibialis anterior (TA) sternomastoid and cleidomastoid muscles from each animal were used for immunohistochemical analysis of fibre size and number, while innervation status was determined for soleus and EDL only. Fibre number, size, innervation status and myotendinous junction (MTJ) length were all investigated using immunohistochemistry. Fibre number, size and MTJ were determined from cross sections of snap-frozen muscles, fluorescently labeled and digitally photographed and processed. Innervation status was determined from longitudinal sections from snap-frozen muscle, fluorescently labeled and digitally photographed and processed. I found that both soleus and EDL exhibited age-related decline in innervation, but that this was not associated with fibre atrophy in either of these muscles. Fibre number of soleus but not EDL declined in an age-dependent manner (21%). Endurance exercise had no effect on EDL, but resulted in increased neuromuscular junction health for soleus. While two months of running did not significantly prevent decline in fibre number, four months of running successfully maintained fibre number of soleus similar to that of young controls. A previously undescribed remodeling of MTJ was found to increase MTJ length with age, which is thought to account for much of the age-related fibre loss. MTJ lengthening was prevented by both two and four months of running in elderly mice. In summary, I found that both soleus and EDL exhibited age-related denervation, but that reduction in fibre number was a feature of the soleus muscle only. I found that endurance exercise maintains muscle mass in the old soleus primarily by means of preventing age- related remodeling of the MTJ, and that these changes to the MTJ may account for much of the age-related fibre loss reported in soleus