Biology

Long Term mTORC1 Inhibition Slows Muscle Aging in Mice via Preservation of Neuromuscular Junctions


Sarcopenia is the name given to the characteristic loss of muscle mass and strength that occurs in later life, the result of numerous contributing processes of damage and decline. Researchers here find that long-term treatment with rapamycin, and thus likely other more targeted approaches to mTORC1 inhibition, slows the onset of sarcopenia in mice by preserving the function of neuromuscular junctions, the links between nerves and muscles. The most important contributing cause of sarcopenia is likely to be a slowdown in muscle stem cell activity. Interestingly, these stem cell populations appear to remain viable, but are increasingly quiescent in response to the damaged and inflammatory environment of aged tissues. This work suggests that damage and declining function of neuromuscular junctions should be given a greater weight than previously considered, however.

Recently, nine processes involved in aging were proposed, 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. 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. Overactivity of the mammalian (or mechanistic) target of rapamycin complex 1 (mTORC1) is central to many of these processes, and dampening mTORC1 activity by its allosteric inhibitor rapamycin is one of the most effective interventions to prolong life. However, mTORC1 activity is also required for muscle hypertrophy. 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.

In previous work, we have shown that mTORC1 activity must be finely balanced in skeletal muscle. Here, we demonstrate that long-term rapamycin treatment is overwhelmingly positive in aging skeletal muscle, preserving muscle size, function, and neuromuscular junction (NMJ) integrity. Interestingly, responsiveness to rapamycin differs between muscles, suggesting that the primary drivers of age-related muscle loss may differ between muscles. 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. Our data point to age-related NMJ instability as a focal point of mTORC1-driven sarcopenia. Maintenance of NMJ structure and transmission efficiency is crucial for preserving muscle function at high age.

Link: https://doi.org/10.1038/s41467-020-18140-1

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