MTORC1 underlies age-related muscle fiber damage and loss by inducing oxidative stress and catabolism.

Huibin Tang,Joseph B Shrager,Michael Kim,Xuhuai Ji,Kun Wang,Myung Lee,Hideki Okazawa,Daniel Goldman,Ken Inoki,Catherine L Kennedy,Susan V Brooks,Yoyo Wang,Junying Wang,Sabrina Van Roekel,Thomas A Rando,Richard A Miller,Junqin Zhu ,Zelton Dave Sharp ,Peter Macpherson ,Danielle Fraga ,Kun Liang Guan

doi:10.1111/acel.12943

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.

Highlights

Age‐dependent loss of skeletal muscle mass and function, that is, sarcopenia, is an increasingly significant public health concern as av‐ erage life expectancy increases
The level of mTORC1 ac‐ tivity in muscle fibers is closely associated with phenotypic changes that occur in naturally aging muscle
To understand how activated mTORC1 leads to muscle damage and loss, we examined a TSC1‐null mouse model (Bentzinger et al, 2013; Castets et al, 2013; Tang et al, 2014)

Summary

| INTRODUCTION

Age‐dependent loss of skeletal muscle mass and function, that is, sarcopenia, is an increasingly significant public health concern as av‐ erage life expectancy increases. The occurrence of these abnormal degenerative phenotypes in skeletal muscle fibers from older mice and humans that have increased pS6 staining indicates that elevated mTORC1 ac‐ tivity in aging muscle fibers is associated with muscle fiber damage These degenerative processes, resulted in part from the activation of apoptotic signaling, contribute to the age‐related muscle atrophy. The genes involved in mitochondrial oxida‐ tive stress and programmed cell death are dramatically induced, but primarily only at 18 months This reveals a progressive induction of oxidative stress and apoptosis in skeletal muscle following chronic mTORC1 activation. The upregulated transcriptional expression of GDF15 and FoxO3 mRNAs was completely normalized by rapamycin treatment (Figure 5c) Both the molecular and the phenotypic changes within skeletal muscle which are present in TSC1 ko mice are prevented by rapamycin treatment, indicating that the changes observed in TSC1 ko mice are due to the activation of mTORC1.

GDF15 siRNA 4

| DISCUSSION

Findings

| MATERIALS AND METHODS