Problem Statement:

 

Sarcopenia, characterized by age-related declines in muscle mass and function, poses significant health risks in older adults, leading to reduced mobility, frailty, and diminished quality-of-life (1). The mechanistic target of rapamycin complex 1 (mTORC1), is a master regulator of muscle mass that becomes hyperactivated in ageing muscles (2), leading to impaired proteostasis (3). Indeed, animal studies show that suppression of the mTORC1 pathways can mitigate aspects of sarcopenia (4). We investigated the impacts of Rapamune therapy on skeletal muscle physiology under both rested and exercised conditions in humans.

 

Methodology:

 

Thirteen male participants (64±6 y, BMI: 26±2 kg/m²) were included in this analysis following ethical approval (FMHS 90-0820) and clinical trials registration (NCT05414292). Exclusion criteria were cardiovascular, cerebrovascular, respiratory, metabolic, neurological, and musculoskeletal conditions, in addition to clinical contraindications to Rapamune (e.g., immunosuppression). Participants were randomly assigned to either: ‘Rapamune’ (rapamycin) (n=7) receiving 1 mg (pill form) daily, or placebo (n=6) (a lactose pill). The intervention lasted 4-months, with participants undergoing unilateral resistance exercise training (3x/week, knee-extension with the dominant leg, 75% 1-repetition maximum). Muscle architecture [non and exercised-legs] of the vastus lateralis (VL) was assessed by ultrasonography (cross-sectional area (CSA) and muscle thickness (MT)) before and after the intervention. Strength was evaluated by maximum voluntary contraction (MVC) of the knee extensors. Data were analysed by ANOVA; p<0.05 was considered significant.

 

Results:

 

In the untrained legs, no significant changes in MT were found in either the Rapamune (2.44 vs 2.40 cm, p=0.86) or placebo groups (2.18 vs. 2.09 cm, p=0.624) over the 4-month intervention period. However, when examining CSA, the Rapamune group exhibited a significant increase over the 4-month period (26.64 vs. 29.19 cm², p=0.01), while no significant changes were observed in the placebo group (22.49 vs. 23.80 cm², p=0.29). In-keeping with this, MVC increased in the Rapamune untrained legs (374 vs. 464 N, p=0.007), while no significant changes were observed in the placebo untrained legs (392 vs. 400 N, p=0.75). In the trained legs, there were no changes in MT in either the Rapamune (2.59 vs 2.67 cm, p=0.53) or placebo (2.21 vs. 2.30 cm, p=0.43) groups over the 4-month intervention. Similarly, no significant differences were found in CSA in either the Rapamune (27.9 vs. 29.4 cm², p=0.09) or placebo group (23.2 vs. 24.2 cm², p=0.34), albeit with a tendency for Rapamune to increase muscle CSA (p<0.1). MVC increased in the Rapamune group only (349 vs. 489 N p=0.003), (placebo: 393 vs. 426 N, p=0.63).

 

Conclusion:

 

Rapamune may improve both muscle dimensions and function in trained and untrained states. This work appears to substantiate the potential benefits of dampening mTORC1 signalling to mitigate age-related neuro/muscular declines under rested and exercised conditions. Ongoing research will explore larger sample sizes, mechanisms, and clinically important outcomes, such as mobility and balance. Diversifying ethnicity and sex of participants in order to validate Rapamune’s therapeutic potential for sarcopenia treatment are also key next steps.