Journal Article

The neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia

Reinhard, Judith R., Handschin, Christoph, Kaiser, Marco S., Guridi, Maitea, Zavolan, Mihaela, Weihrauch, Martin, Wang, Xueyong, Delezie, Julien, Rich, Mark M., Tintignac, Lionel A., Lin, Shuo, Battilana, Fabienne, Sinnreich, Michael, Thürkauf, Marco, Mittal, Nitish, Ham, Daniel J., Rüegg, Markus A., Börsch, Anastasiya

2020

Overview

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. mTORC1 expression is increased during ageing of muscle, and on the other hand, its activation promotes muscle hypertrophy. Here, the authors assess whether mTORC1 has positive or negative effects on ageing, and show that its long-term inhibition preserves muscle mass and function and neuromuscular junction integrity, whereas muscle-specific activation is associated with sarcopenia.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38/91 / 631/443/319 / 631/443/7 / 64/60 / 692/698/1671/1668/1973 / Activation / Aging / Aging - drug effects / Aging - physiology / Animals / Cell Line / Developed countries / Disease Models, Animal / Electromyography / Gene expression / Gene Expression Regulation - drug effects / Gene Expression Regulation - physiology / Humanities and Social Sciences / Humans / Hypertrophy / Laser Capture Microdissection / Life span / Male / Mechanistic Target of Rapamycin Complex 1 - antagonists & inhibitors / Mechanistic Target of Rapamycin Complex 1 - genetics / Mechanistic Target of Rapamycin Complex 1 - metabolism / Mice / multidisciplinary / Muscle Fibers, Skeletal - pathology / Muscles / Musculoskeletal system / Myoblasts / Neuromuscular Junction - drug effects / Neuromuscular Junction - pathology / Neuromuscular system / Patch-Clamp Techniques / Rapamycin / RNA-Seq / Sarcopenia / Sarcopenia - genetics / Sarcopenia - pathology / Sarcopenia - physiopathology / Sarcopenia - prevention & control / Science / Science (multidisciplinary) / Signal Transduction - drug effects / Signal Transduction - genetics / Sirolimus - administration & dosage / Skeletal muscle