Abstract
With human median lifespan extending into the 80s in many developed countries, the societal burden of age-related muscle loss (sarcopenia) is increasing. mTORC1 promotes skeletal muscle hypertrophy, but also drives organismal aging. Here, we address the question of whether mTORC1 activation or suppression is beneficial for skeletal muscle aging. 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. 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 (https://sarcoatlas.scicore.unibas.ch/), as a user-friendly gene discovery tool. 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.
Highlights
With human median lifespan extending into the 80s in many developed countries, the societal burden of age-related muscle loss is increasing. mTORC1 promotes skeletal muscle hypertrophy, and drives organismal aging
We identify the neuromuscular junction (NMJ) as a focal point of skeletal muscle responses to aging and mTORC1 signaling, and create SarcoAtlas, a comprehensive, publicly available resource to further our understanding of the molecular mechanisms involved in sarcopenia
MRI recordings of body composition showed that the accentuated loss of body mass in rapamycin-treated mice was the result of lean mass loss, rather than fat mass loss, which markedly declined in both control and rapamycin groups (Fig. 1c, d and Supplementary Fig. S1A)
Summary
With human median lifespan extending into the 80s in many developed countries, the societal burden of age-related muscle loss (sarcopenia) is increasing. mTORC1 promotes skeletal muscle hypertrophy, and drives organismal aging. 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. To dissect the key signaling nodes associated with mTORC1-driven sarcopenia, we create a comprehensive multimuscle gene expression atlas from (1) adult (10-months old), (2) geriatric (30-months old), and (3) geriatric, rapamycin-treated mice using mRNA-seq We integrate these data with gene expression profiles of muscle from TSCmKO mice and synaptic and extra-synaptic regions. We identify the NMJ as a focal point of skeletal muscle responses to aging and mTORC1 signaling, and create SarcoAtlas, a comprehensive, publicly available (https://sarcoatlas.scicore.unibas.ch/) resource to further our understanding of the molecular mechanisms involved in sarcopenia. We conclude that overactivity of skeletal muscle fiber mTORC1 fulfils the three criteria necessary to be a hallmark of sarcopenia, and thereby firmly establish the TSCmKO mouse as a model of accelerated sarcopenia
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