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

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.

Molecular and phenotypic analysis of rodent models reveals conserved and species-specific modulators of human sarcopenia

“…By 28 months, the muscle mass decreased by 19.7% in the tibialis anterior and 29.6% in the quadriceps, compared to 8-18 months-old mice. Muscle loss outstripped body mass loss for all measured muscles, with the notable exception of the tibialis anterior, which was comparatively more resistant to age-related muscle loss, as previously observed in both humans 12 and mice 27 . Analysis of internal organs showed a maintenance (liver) or increase (heart) of other lean-tissue organs (Fig.…”

“…1e), explaining the overall maintenance of whole-body lean mass. Indeed, seminal vesicles, although not measured, were notably larger in older mice, as previously observed 27 . In contrast, and consistent with MRI measures of body composition, epididymal fat depositions were measurably lower in 22-28 months-old mice than 8-18 months-old mice, reaching a body mass normalized reduction of 81.6 ± 2.8% at 28 months.…”

“…Common to mice and humans were pathways linked to the mechanistic target of rapamycin complex-1 (mTORC1), which controls the balance between protein synthesis and degradation in literally all tissues. mTORC1 activity increases during skeletal muscle aging [50][51][52] ; its long-term inhibition with rapamycin extended the mouse lifespan 53 , and positively impacted the skeletal muscle of mice 25 . Our study supports the notion that the mouse is a good model for studying the dynamics of mTORC1 signaling during aging.…”

“…We further infer the transcription factors (TFs) underlying these gene expression changes, which could be pursued in animal models for the development of new therapies. Finally, we integrate the muscle transcriptome profiles of mice and rats analyzed in this study into "SarcoAtlas" (https:// sarcoatlas.scicore.unibas.ch/), a resource which we have established to support further analyses of molecular mechanisms underlying sarcopenia 25 .…”

On the mechanisms underlying attenuated redox responses to exercise in older individuals: A hypothesis

“…Various researchers have reported loss of innervation of individual fibers in aged muscles, including our study which indicated that ~15% of individual muscle fibers from old mice are completely denervated and ~80% of NMJs showed some disruption [ 21 ]. Maintenance of the NMJ is increasingly seen to be key to interventions that may maintain muscle mass and function in older age [ 22 ].…”