Impacts of Mechanistic Target of Rapamycin (mTOR) inhibition on aged human muscle

Active: 2020.03.01 - 2021.09.30
UK SPINE Scientific Liaison: Monica Spisar

Large-scale studies demonstrate that skeletal muscle mass and functional capacity are fundamentally important for healthy ageing. With ageing, approximately 30% of an individual's peak skeletal muscle mass is lost by age 80-years. This age associated muscle loss (sarcopenia) is of significant relevance to the maintenance of good health, with reduced muscle mass and function being associated with increased cancer-related deaths, delayed post-operative recovery and reduced independence, amongst others. At present, other than weight-lifting exercise, no effective strategies exist to counteract sarcopenia.

A potential intervention is to use a compound which has already been shown in animal models to improve skeletal muscle preservation with ageing. One such compound acts by inhibiting mechanistic target of rapamycin (mTOR), a molecule which is involved in the maintenance of healthy muscle; in older muscle, this molecule becomes overactive and there is evidence that this hyper-activity becomes harmful. This research will determine proof-of-concept for the potential of mTOR inhibition in relation to ameliorating human frailty.

In this study, the compound (rapamycin/Sirolimus) used to “block mTOR” is derived from the Streptomyces hygroscopicus bacteria. Crucially, this compound is safe to provide to older humans, although its use in relation to human ageing remains unexplored from a scientific and clinical perspective. The compound will be administered to older people and evidence of "anti-ageing" properties in relation to human muscle will be interrogated. This research will be conducted alongside exercise training to determine interactions with muscle activity.

The scientific objectives are to:

A. Determine the impacts of rapamycin upon human muscle mass by investigating:

1. Whole body muscle mass by DXA and MRI;
2. Whole body muscle mass by D3 creatine tracer;
3. Ultrasound of thigh muscles.

B. Determine the impacts of rapamycin treatment on muscle function by investigating:

1. Muscle strength as MVC/1-RM;
2. Muscle power;
3. Muscle performance as short performance physical battery testing;
4. Muscle-nerve cross-talk.

C. Determine the impacts of rapamycin treatment on muscle metabolism by investigating:

1. Effects on muscle protein synthesis;
2. Effects on muscle protein breakdown;
3. Regulatory pathways of muscle protein turnover.