TY - JOUR
T1 - Long-term PGC1β overexpression leads to apoptosis, autophagy and muscle wasting
AU - Sopariwala, Danesh H.
AU - Yadav, Vikas
AU - Badin, Pierre Marie
AU - Likhite, Neah
AU - Sheth, Megha
AU - Lorca, Sabina
AU - Vila, Isabelle K.
AU - Kim, Eun Ran
AU - Tong, Qingchun
AU - Song, Min Sup
AU - Rodney, George G.
AU - Narkar, Vihang A.
N1 - Funding Information:
We would like to thank Dr. Zhengmei Mao from the IMM imaging core for her assistance with Amira software and microscopy. This work was supported by UTHealth intramural funds and The Welch Foundation endowment in Chemistry & Related Science (#L-AU-0002), and a grant from National Institute of Health/National Heart Lung and Blood Institute (1 R01 HL129191-01) to V.A.N. The funding bodies did not have any role in the study design, data collection, analysis or interpretation, writing the report and in the decision to submit the manuscript for publication.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - Skeletal muscle wasting is prevalent in many chronic diseases, necessitating inquiries into molecular regulation of muscle mass. Nuclear receptor co-activator peroxisome proliferator-activated receptor co-activator 1 alpha (PGC1α) and its splice variant PGC1α4 increase skeletal muscle mass. However, the effect of the other PGC1 sub-type, PGC1β, on muscle size is unclear. In transgenic mice selectively over-expressing PGC1β in the skeletal muscle, we have found that PGC1β progressively decreases skeletal muscle mass predominantly associated with loss of type 2b fast-twitch myofibers. Paradoxically, PGC1β represses the ubiquitin-proteolysis degradation pathway genes resulting in ubiquitinated protein accumulation in muscle. However, PGC1β overexpression triggers up-regulation of apoptosis and autophagy genes, resulting in robust activation of these cell degenerative processes, and a concomitant increase in muscle protein oxidation. Concurrently, PGC1β up-regulates apoptosis and/or autophagy transcriptional factors such as E2f1, Atf3, Stat1, and Stat3, which may be facilitating myopathy. Therefore, PGC1β activation negatively affects muscle mass over time, particularly fast-twitch muscles, which should be taken into consideration along with its known aerobic effects in the skeletal muscle.
AB - Skeletal muscle wasting is prevalent in many chronic diseases, necessitating inquiries into molecular regulation of muscle mass. Nuclear receptor co-activator peroxisome proliferator-activated receptor co-activator 1 alpha (PGC1α) and its splice variant PGC1α4 increase skeletal muscle mass. However, the effect of the other PGC1 sub-type, PGC1β, on muscle size is unclear. In transgenic mice selectively over-expressing PGC1β in the skeletal muscle, we have found that PGC1β progressively decreases skeletal muscle mass predominantly associated with loss of type 2b fast-twitch myofibers. Paradoxically, PGC1β represses the ubiquitin-proteolysis degradation pathway genes resulting in ubiquitinated protein accumulation in muscle. However, PGC1β overexpression triggers up-regulation of apoptosis and autophagy genes, resulting in robust activation of these cell degenerative processes, and a concomitant increase in muscle protein oxidation. Concurrently, PGC1β up-regulates apoptosis and/or autophagy transcriptional factors such as E2f1, Atf3, Stat1, and Stat3, which may be facilitating myopathy. Therefore, PGC1β activation negatively affects muscle mass over time, particularly fast-twitch muscles, which should be taken into consideration along with its known aerobic effects in the skeletal muscle.
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U2 - 10.1038/s41598-017-10238-9
DO - 10.1038/s41598-017-10238-9
M3 - Article
C2 - 28860475
AN - SCOPUS:85028712987
SN - 2045-2322
VL - 7
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 10237
ER -