Interestingly, responsiveness to rapamycin differs between muscles, suggesting that the primary drivers of age-related muscle loss may differ between muscles. Here, we demonstrate that long-term rapamycin treatment is overwhelmingly positive in aging skeletal muscle, preserving muscle size, function, and neuromuscular junction (NMJ) integrity. Thus, it remains an open question as to whether activation or inhibition of mTORC1 could counteract sarcopenia. Finally, rapamycin ameliorates muscle function in a number of muscular dystrophies 19, 20. In rodents, mTORC1 activity is high in sarcopenic compared to adult muscle 13, 14, 15, 16, 17, and the same has been seen in human biopsies 18. However, rather than developing hypertrophic muscles, TSCmKO mice experience dysregulated proteostasis and develop a late-onset myopathy 11, 12. On the other hand, constitutive, skeletal muscle-specific knockout of tuberous sclerosis complex 1 (TSC1), an upstream inhibitor of mTORC1, in mice (TSCmKO) leads to sustained activation of mTORC1 and increased protein synthesis. Likewise, specific depletion of raptor in muscle progenitors severely impacts muscle development and is prenatally lethal 10. Constitutive, muscle-specific depletion of mTOR or the mTORC1 component raptor induces severe myopathy 8, 9.
In previous work, we have shown that mTORC1 activity must be finely balanced in skeletal muscle. Therefore, there is concern that suppressing mTORC1 to extend lifespan could be at the expense of skeletal muscle function, thereby extending the “poor-quality” period of life 7. However, mTORC1 activity is also required for muscle hypertrophy 5, 6. Overactivity of the mammalian (or mechanistic) target of rapamycin complex 1 (mTORC1) is central to many of these processes 3, and dampening mTORC1 activity by its allosteric inhibitor rapamycin is one of the most effective interventions to prolong life 4. Each biological process fulfils three hallmark criteria: (1) it occurs during normal aging, (2) intensifying the process accelerates aging, and (3) dampening the process delays aging. Recently, nine processes involved in aging were proposed 2, namely cellular senescence, stem cell exhaustion, genomic instability, telomere attrition, loss of proteostasis, deregulation of nutrient sensing, epigenetic alterations, mitochondrial dysfunction, and altered intracellular communication. Sarcopenia constrains physical activity, degrades the quality of life, and is a major burden on society 1. Rapid advances in treating life-threatening, age-related diseases, such as cancer and cardiovascular disease, have extended human lifespan in many countries, but exposed other age-related diseases, including sarcopenia, the age-related loss of muscle mass and strength. We uncover inter-muscle divergence in the primary drivers of sarcopenia and identify the neuromuscular junction as a focal point of mTORC1-driven muscle aging. Through integration of comprehensive physiological and extensive gene expression profiling in young and old mice, and following genetic activation or pharmacological inhibition of mTORC1, we establish the phenotypically-backed, mTORC1-focused, multi-muscle gene expression atlas, SarcoAtlas (), as a user-friendly gene discovery tool.
We demonstrate that chronic mTORC1 inhibition with rapamycin is overwhelmingly, but not entirely, positive for aging mouse skeletal muscle, while genetic, muscle fiber-specific activation of mTORC1 is sufficient to induce molecular signatures of sarcopenia. Here, we address the question of whether mTORC1 activation or suppression is beneficial for skeletal muscle aging. mTORC1 promotes skeletal muscle hypertrophy, but also drives organismal aging. With human median lifespan extending into the 80s in many developed countries, the societal burden of age-related muscle loss (sarcopenia) is increasing.
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