mTORC1 underlies age‐related muscle fiber damage and loss by inducing oxidative stress and catabolism

Abstract

Aging leads to skeletal muscle atrophy (i.e., sarcopenia), and muscle fiber loss is a critical component of this process. The mechanisms underlying these age‐related changes, however, remain unclear. We show here that mTORC1 signaling is activated in a subset of skeletal muscle fibers in aging mouse and human, colocalized with fiber damage. Activation of mTORC1 in TSC1 knockout mouse muscle fibers increases the content of morphologically abnormal mitochondria and causes progressive oxidative stress, fiber damage, and fiber loss over the lifespan. Transcriptomic profiling reveals that mTORC1's activation increases the expression of growth differentiation factors (GDF3, 5, and 15), and of genes involved in mitochondrial oxidative stress and catabolism. We show that increased GDF15 is sufficient to induce oxidative stress and catabolic changes, and that mTORC1 increases the expression of GDF15 via phosphorylation of STAT3. Inhibition of mTORC1 in aging mouse decreases the expression of GDFs and STAT3's phosphorylation in skeletal muscle, reducing oxidative stress and muscle fiber damage and loss. Thus, chronically increased mTORC1 activity contributes to age‐related muscle atrophy, and GDF signaling is a proposed mechanism.

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

“…However, rather than developing hypertrophic muscles, TSCmKO mice experience dysregulated proteostasis and develop a late-onset myopathy 11,12 . 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 . Finally, rapamycin ameliorates muscle function in a number of muscular dystrophies 19,20 .…”

Longevity‐related molecular pathways are subject to midlife “switch” in humans

“…In model organisms, regulators of longevity and health span have been extensively validated (De Haes et al, ; Schaar et al, ); these include inhibition of mTOR (Lamming, Ye, Sabatini, & Baur, )—a nutrient and growth factor sensing, GTPase regulated protein complex (Pan & Finkel, ), which regulates “protective” autophagy programs (Yang et al, ), and strategies down‐regulating mitochondrial components accompanied by modest increases in reactive oxygen species (ROS) production (Arriola Apelo et al, ; Lamming et al, ). Interestingly, activation of the mTOR pathway has been reported in Alzheimer's disease (AD; Tramutola et al, ) and excessive TORC1 activity may contribute to muscle degeneration (Tang et al, ). In humans, age‐related molecular changes are typically modeled using linear methods, yet in shorter‐lived organisms (Hall et al, ; Manczak, Jung, Park, Partovi, & Reddy, ; Rana et al, ; Rangaraju et al, ; Yang & Hekimi, ) nonlinear molecular responses to age are observed (Rangaraju et al, ), featuring the aforementioned canonical pathways (Lamming et al, ; Pan & Finkel, ).…”

The TOR Pathway at the Neuromuscular Junction: More Than a Metabolic Player?

“…Indeed, sarcopenic muscle shows impaired or delayed response to anabolic stimuli, such as amino acids, IGF-1 injection, exercise or electric stimulation [“anabolic resistance” – ( Guillet et al, 2004 ; Parkington et al, 2004 ; Cuthbertson et al, 2005 ; Funai et al, 2006 ; Kumar et al, 2009 ; Fry et al, 2011 ; Burd et al, 2013 ; Barclay et al, 2019 )]. However, several studies also point to higher basal mTORC1 activation in aged or sarcopenic rodent muscle ( Barns et al, 2014 ; Baar et al, 2016 ; White et al, 2016 ; Joseph et al, 2019 ; Tang et al, 2019 ; Ham et al, in press ) and in humans ( Markofski et al, 2015 ), which may mediate the blunted response to nutrition and exercise. The up-stream factors leading to mTORC1 activation with aging remain elusive.…”

“…Surprisingly, inhibition of mTORC1 by rapamycin or rapalogs is also sufficient to reverse age-associated muscle alterations. In particular, rapamycin/rapalogs limit NMJ alterations and restore autophagic flux ( Joseph et al, 2019 ; Tang et al, 2019 ; Ham et al, in press ). Although consistent with the overall beneficial impact of rapamycin on organismal aging, further investigation focusing on the distinct effects of these drugs on different muscles and on the consequences of inhibiting mTORC1 signaling pathway on muscle mass and function will be essential.…”

“…TOR ( T arget O f R apamycin ) is at the heart of one of the key signaling pathways responsible for proteostasis. TOR activity is essential for muscle development and growth, however, overactive TOR signaling is also implicated in aging and sarcopenia ( Tang et al, 2019 ; Ham et al,in press ) and suppressing TOR by pharmacological or nutritional means remains a primary target of anti-aging interventions. While TOR is well known for its role in metabolism and aging, its role in NMJ development and maintenance is less well described.…”