Plasticity and function of human skeletal muscle in relation to disuse and rehabilitation: Influence of ageing and surgery

In order to study the influence of disuse and aging on skeletal muscle homeostasis, different human models were employed. Effects of chronic disuse were investigated in elderly patients suffering from uni-lateral hip-osteoarthritis, whereas the effect of short-term disuse (4 and 14 days of unilateral lower limb immobilisation) was assessed in healthy young and old individuals. In summary, chronic muscle disuse in the elderly was associated with marked quantitative as well as qualitative neuromuscular impairments. More specifically, decreases were observed in muscle strength, quadriceps muscle size and myofibre area, muscle architecture, contractile properties and neuromuscular activation. Furthermore, substantial side-to-side differences in specific strength (MVC/LCSA) and normalised rapid muscle force capacity (RFD/CSA) were observed, indicating that a significant part of the observed changes in mechanical muscle function with disuse were explained by impairments in muscle quality. Importantly, within the first 4 days of immobility the ob-served atrophy responses did not seem affected by age, as manifested by comparable reductions in myofibre area in young and old individuals. However, in line with previous observations using various animal models, we observed a larger loss in muscle mass in young compared to older individuals after more prolonged immobilisation (14 days). Conversely, old individuals were more negatively affected with respect to neural function and rapid force characteristics than their young counterparts. Moreover, we showed that the initiation and regulation of human skeletal muscle atrophy with short-term disuse is age-dependant. Based on the present experiments it can be concluded that a multitude of signalling pathways related to both muscle atrophy and protein synthesis are activated in the initial phase of disuse, which in turn lead to a rapid initial atrophy response (~1-4 days) in both young and old individuals followed by a gradually attenuated atrophy response at later time-points (~2 weeks). Notably, during the first 1-2 days of immobility a parallel activation of the ubiquitin-proteasome pathway and the IGF-1/Akt pathway seem to occur along with a deactivation of PGC-1α and PGC-1β, suggesting that cellular proteolysis plays an important role in the initiation of human disuse atrophy in both young and old muscle, whereas the concurrent regulation in protein synthesis signalling and proteolysis inhibition appears to affect young adults more pronouncedly compared to older adults. Gaining a better understanding of the ability of human skele-tal muscle to recover from disuse-induced atrophy has important implications for the development and implementation of effective countermeasures against physical frailty in the increasing population of elderly. Importantly therefore, the present experiments demonstrate that resistance training is highly effective of increasing maximal muscle strength and neuromuscular function in elderly post-operative patients. Importantly, these increases in mechanical muscle function were accompanied by gains in muscle size, architecture and in the expression of IGF-I mRNA splice variants, resembling that typically seen in young healthy individuals when exposed to resistance training. In contrast, these positive adaptations could not be achieved with the use of neuromuscular electrical stimulation or conventional rehabilitation efforts alone. Collectively, these findings strongly underline the importance of implementing resistive exercises in future rehabilitation programs for elderly individuals. In addition, comparing young and old able-bodied individuals, we observed that the magnitude and time-course of changes in mechanical muscle function during the recovery phase following short-term disuse were compromised in old compared to young individuals. Likewise, aged individuals demonstrated an impaired response to re-loading reflected by attenuated gains in myofibre area, in parallel with smaller increases in satellite cell number despite no age-related differences were observed in factors known to promote skeletal muscle hypertrophy and myogenic stem cell proliferation (IGF-Ea, MGF, MyoD, myogenin, HGF). Moreover, an age-specific regulation in myostatin mRNA expression was observed, characterized by an amplified increase in aging skeletal muscle with immobilisation that was followed by less down-regulation during the subsequent phase of re-loading. In combination with an association observed between the changes in myostatin expression and satellite cell proliferation in the acute phase of re-loading, these data indicates that myostatin play an important role in the impaired ability of aged human skeletal muscle.