Author(s): MEMIS, H., JONES, E., ANYIAM, O., PHILLIPS, B., IDRIS, I., PIASECKI, M., SMITH, K., WILKINSON, D., ATHERTON, P., Institution: UNIVERSITY OF NOTTINGHAM, Country: UNITED KINGDOM, Abstract-ID: 2708

INTRODUCTION:
Sarcopenia contributes to frailty, impaired mobility, and reduced quality of life. mTOR is prototypical positive regulator of muscle anabolism; however, its ‘hyperactivity’ in ageing may counterintuitively disrupt proteostasis e.g., preclinical evidence indicates mTOR inhibition unexpectedly attenuate sarcopenic phenotypes. We for the first time, investigated the effects of rapamycin therapy on human muscle physiology under rested and resistance-trained conditions.
METHODS:
Healthy male participants (n=22, 65.8 ± 7.7y, BMI: 26.4 ± 2.7 kg/m²; n.b. single sex initially due to funding constraints and unpredictable potential for sexual dimorphism) were included in this analysis following ethical approval (FMHS 90-0820) and clinical trials registration (NCT05414292). Participants were randomly assigned to either: ‘Rapamune’ (rapamycin) (n=11) receiving 1 mg (pill-form) daily, or placebo (n=11) (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 of the vastus lateralis 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, with p<0.05 considered significant.
RESULTS:
In the untrained-state, no changes in MT were seen in Rapamune (2,43 ± 0,19 vs 2,41 ± 0,16 cm, p=0.95) or placebo groups (2,06 ± 0,39 vs 1,98 ± 0,46 cm, p=0.39). However, CSA, better reflecting gross muscle architecture, increased in the Rapamune group (26,04 ± 2,17 vs 29,05 ± 2,11 cm², p<0.0001), despite no changes being observed in the placebo group (21,23 ± 4,86 vs 21,98 ± 4,84 cm², p=0.34). MVC increased in the Rapamune untrained-state (398 ± 87 vs 490 ± 124 N, p<0.0001), and also increased in the placebo group (382 ± 88 vs 421,05 ± 100 N, p=0.048. In the trained-state, there were no changes in MT in either the Rapamune (2,51 ± 0,16 vs 2,62 ± 0,14 cm, p=0.20) or placebo (2,15 ± 0,44 vs 2,09 ± 0,49 cm, p=0.62) groups. CSA increased in the Rapamune group (27,75 ± 3,46 vs 30,48 ± 4,13 cm², p=0.0004), with no changes being observed in the placebo group (21,79 ± 4,82 vs 23,05 ± 4,94 cm², p=0.11). MVC increased in the Rapamune group (384,00 ± 108,90 vs 505,91 ± 119,51 N, p=0.0001), with no changes in placebo (411,27 ± 124,41 vs 457,45 ± 122,41 N, p=0.13).
CONCLUSION:
Our findings represent the first to support the concept that dampening mTORC1 signalling could facilitate, not hinder, age-related neuromuscular declines in humans. In terms of muscle mass, discordance between MT and CSA via ultrasound requires MRI validation and ongoing work will address this. As will be probing molecular mechanisms, translational relevance in more diverse cohorts, and key clinical outcomes (e.g., mobility, balance, and physical function).