Impacts of Mechanistic Target of Rapamycin (mTOR) Inhibition on Aged Human Muscle.

Skeletal muscle is known for its role in locomotion however, muscles are also important for maintaining whole-body metabolic health. Skeletal muscles represent a vast protein store, the amino acids from which can be broken down in times of fasting, infection and disease in order to provide energy and amino acids to maintain other critical organs. With increases in the ageing population, this will inevitably increase age-related co-morbidities, and also the prevalence of frailty and increased healthcare costs.

A major facet of frailty is skeletal muscle atrophy and loss of function, and critically, these are associated with poorer clinical outcomes (e.g. surgery), so mitigating age-related muscle loss is crucial for healthy ageing. The processes of muscle loss with ageing in humans are a combination of neurodegeneration of lower motor neurons and concomitant muscle fibre atrophy. While the underlying mechanisms of age-related muscle loss are unclear, a reduced responsiveness to key environmental cues, namely nutrition and movement ("anabolic resistance"), would appear to be central. To date, no pharmaceuticals have yielded the necessary safety and efficacy effects to mitigate age-related muscle loss so exercise, particularly resistance exercise training (RET), remains the most established intervention to improve muscle mass and function in older people. Nonetheless, not all older people can perform RET, and muscle growth responses to RET are diminished in older age. As such, the search for interventions to mitigate muscle ageing and maximise responses to exercise pre-/rehabilitation in terms of muscle growth and function remain key.

The mechanistic target of rapamycin (mTOR) is often termed a "master regulator" in relation to skeletal muscle homeostasis and exists in two distinct complexes, mTORc1 and mTORc2. The most established role of mTORc1 in muscle is as a cellular sensor of nutrients and movement, where signals are conveyed to mTOR substrates, regulating the rate of mRNA translation and thus muscle protein synthesis (MPS). mTOR activity is required for the stimulation of MPS by intake of dietary proteins or free amino acids, in addition to contractile activity, and as such is commonly thought of as being positive in relation to muscle mass. Additionally, administration of rapamycin (a naturally occurring compound that inhibits mTORc1) alongside exercise or nutrient-intake has been shown to reduce the stimulation of MPS. However, confounding the notion of a positive role of mTOR on skeletal muscle, hyper-activation of mTOR has been shown in both ageing rodent and human muscle, suggesting that mTOR signalling has negative impacts in relation to muscle maintenance in ageing.

Despite the positive effects of mTOR in relation to the stimulation of MPS, in animal models data suggest that pharmacological attenuation of mTOR signalling can counteract several age-related diseases and co-morbidities, and increase overall health-span. The major negative ageing traits found to be lessened by dampening mTOR signalling (i.e. with rapamycin) are related to the immune system, organ morphology, neo-plastic disease and neurological dysfunction e.g. motor control. From these studies, the beneficial effects of rapamycin on health-span are clear, but this contrasts the positive impacts mTOR signalling have on muscle. Inhibition of mTOR would be predicted to negatively impact muscle protein turnover however, this is not the case.

Indeed, recent work has challenged the notion of mTOR suppression negatively impacting skeletal muscle metabolism in a number of experimental settings. In pre-clinical models of ageing and/or muscle dysfunction, long-term administration of rapamycin did not negatively impact skeletal muscle mass in mice treated with rapamycin across the life-course. Additionally, long-term administration of rapamycin (9-22 months), showed a mitigation of muscle mitochondrial ageing, reflected by markers of mitochondrial DNA genome stability. Perhaps the most compelling evidence of rapamycin benefiting ageing muscle is from a study where rapalog (a rapamycin analog) treatment was administered to mice where hyper-active mTOR signalling was observed in aged sarcopenic animals, as is also shown in older humans. Crucially, following Rapalog treatment animals demonstrated increases in muscle fibre area in addition to a down-regulation of cellular senescence markers and genes associated with neuromuscular denervation. These works challenge the notion that in older age with mTOR hyper-activation, mTOR-inhibition would have negative effects, and it is now accepted that ageing and age-associated diseases that arise from hyperactive mTORC1 signalling may benefit from mTOR inhibitors. As such, insight into the effects of mTORc1 inhibition are needed in humans, especially in the context of "anabolic resistance", which limits both muscle maintenance and growth potential in older adults. As an immunosuppressant, rapamycin may also present benefits for the treatment of COVID-19 which is a current highly important area of emerging research.