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.
| Original language | English (US) |
|---|---|
| Article number | e12943 |
| Journal | Aging Cell |
| Volume | 18 |
| Issue number | 3 |
| DOIs | |
| State | Published - Jun 1 2019 |
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Keywords
- aging
- mTORC1
- oxidative stress
- signal transduction
- skeletal muscle
ASJC Scopus subject areas
- Aging
- Cell Biology
Cite this
mTORC1 underlies age-related muscle fiber damage and loss by inducing oxidative stress and catabolism. / Tang, Huibin; Inoki, Ken; Brooks, Susan V.; Okazawa, Hideki; Lee, Myung; Wang, Junying; Kim, Michael; Kennedy, Catherine L.; Macpherson, Peter C.D.; Ji, Xuhuai; Van Roekel, Sabrina; Fraga, Danielle A.; Wang, Kun; Zhu, Jinguo; Wang, Yoyo; Sharp, Zelton D; Miller, Richard A.; Rando, Thomas A.; Goldman, Daniel; Guan, Kun Liang; Shrager, Joseph B.
In: Aging Cell, Vol. 18, No. 3, e12943, 01.06.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - mTORC1 underlies age-related muscle fiber damage and loss by inducing oxidative stress and catabolism
AU - Tang, Huibin
AU - Inoki, Ken
AU - Brooks, Susan V.
AU - Okazawa, Hideki
AU - Lee, Myung
AU - Wang, Junying
AU - Kim, Michael
AU - Kennedy, Catherine L.
AU - Macpherson, Peter C.D.
AU - Ji, Xuhuai
AU - Van Roekel, Sabrina
AU - Fraga, Danielle A.
AU - Wang, Kun
AU - Zhu, Jinguo
AU - Wang, Yoyo
AU - Sharp, Zelton D
AU - Miller, Richard A.
AU - Rando, Thomas A.
AU - Goldman, Daniel
AU - Guan, Kun Liang
AU - Shrager, Joseph B.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - 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.
AB - 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.
KW - aging
KW - mTORC1
KW - oxidative stress
KW - signal transduction
KW - skeletal muscle
UR - http://www.scopus.com/inward/record.url?scp=85065892118&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85065892118&partnerID=8YFLogxK
U2 - 10.1111/acel.12943
DO - 10.1111/acel.12943
M3 - Article
C2 - 30924297
AN - SCOPUS:85065892118
VL - 18
JO - Aging Cell
JF - Aging Cell
SN - 1474-9718
IS - 3
M1 - e12943
ER -