Maintaining muscle mass is crucial for health and physical activity. Around age 40, muscle mass begins to decline, potentially leading to sarcopenia, a condition associated with frailty and increased fall risk. Age-related muscle loss is complex and multifactorial. The prevailing view is that this loss is driven by anabolic resistance, which is a reduced capacity to increase muscle protein synthesis (MPS) after anabolic cues, i.e., essential amino acids (EAA) or resistance exercise (REx). Mechanistically, this is thought to be underpinned by dysregulation of the mTORC1 signaling pathway. However, it is unclear whether anabolic resistance contributes to muscle loss in healthy, physically active older adults or if studies supporting this have been confounded by other factors, e.g., inactivity and adiposity. Aging also induces changes at the myocellular level, such as satellite cell loss and morphological alterations, but whether these changes are due to aging itself or lifestyle factors is still being debated.
This thesis examined how anabolic cues impact MPS, mTORC1 signaling, and markers of protein degradation in young and older men. Emphasis was on performing analyses on whole muscle samples and in type I and type II fibers separately. Further aims were to investigate features of muscle fibers in young and older men, focusing on morphology, satellite cells, capillarization, and denervation-reinnervation cycles. The final aim was to develop a valid and fast method for fiber type identification of isolated fibers.
In paper I, the MPS and mTORC1 signaling response was examined in young and older men after EAA intake alone and combined with REx. The results showed comparable rates of MPS across age groups in response to EAA intake, both alone and with REx. Additionally, mTORC1 signaling was similar to or more pronounced in older men compared to younger men. Notably, older men displayed higher levels of amino acid transporters, nutrient sensors, and mTORC1 activators. In paper II, older men had a lesser proportion of type II fibers, smaller and misshaped type II fibers, and fewer satellite cells and capillaries surrounding their type II fibers. Additionally, older men had more denervated and “grouped” muscle fibers compared to young. In paper III, a new method (THRIFTY) for fiber typing individual fibers was developed, proving valid and more time-efficient than reference methods. In paper IV, the THRIFTY method was implemented, and the cell signaling response to intake of EAA alone and combined with REx was examined in pooled type I and type II fibers. The anabolic signaling response was similar or even more pronounced in old compared to young, with a more robust response observed in type I than in type II fibers. No deficits or alterations in autophagic signaling or E3 ligase expression were observed in older adults after EAA intake alone and combined with REx.
In conclusion, healthy, lean, physically active, older men did not display deficits in MPS and mTORC1 signaling after anabolic cues, assessed in whole muscle and pooled type I and type II fibers. This indicates that anabolic resistance is not inherently linked to aging per se. However, older men showed increased expression of amino acid transporters, nutrient sensors, and mTORC1 activators, which may help maintain anabolic sensitivity. Despite exhibiting decrements specifically in type II fibers, such as atrophy and altered shape, there was no impairment in mTORC1 signaling or signaling related to autophagy and proteasomal degradation in these fibers after anabolic stimulation. Other factors, such as denervation and satellite cell deficits, may contribute to muscle loss in this population, but their relative impact remains unclear.