Total Skeletal Muscle PGC-1 Deficiency Uncouples Mitochondrial Derangements from Fiber Type Determination and Insulin Sensitivity

Zechner, Christoph Peter Gerhard; Lai, Ling; Zechner, Juliet F.; Geng, Tuoyu; Yan, Zhen; Rumsey, John W.; Collia, Deanna; Chen, Zhouji; Wozniak, David F.; Leone, Teresa C.; Kelly, Daniel P.

doi:10.1016/j.cmet.2010.12.011

Cited by 48 publications

(72 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The alterations in mitochondrial biogenesis are driven, in part, by PGC‐1α, a major regulator of mitochondrial biogenesis . Mice deficient in PGC‐1α have reduced expression of Mfn2 mRNA . Conversely, up‐regulation in PGC‐1α, from a single bout of cycling exercise stimulated ERRα binding at the −413/−398 motifs on the Mfn2 promoter, resulting in an increase in Mfn2 mRNA during the recovery phase .…”

Section: Discussionmentioning

confidence: 99%

Expression of mitochondrial fission and fusion regulatory proteins in skeletal muscle during chronic use and disuse

et al. 2013

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

Expression of mitochondrial fission and fusion regulatory proteins in skeletal muscle during chronic use and disuse

et al. 2013

View full text Add to dashboard Cite

show abstract

“…After acclimation, exercise endurance test was determined using a treadmill running test, with the speed 10 m/min for 5 min. After the initial warm‐up period, the running velocity was set to 10 m/min for 1 h and increased by 2 m/min increments at every 15 min until mice could not be prompted to continue running by moderate electric stimulation (less than 0.1 mA) and remained at the electrode for at least 10 continuous seconds . Mouse endurance capacity was estimated by running to exhaustion on an Exer4‐OxyMax motorized treadmill (Columbus Instruments, Columbus, OH, USA).…”

Section: Methodsmentioning

confidence: 99%

Hemojuvelin is a novel suppressor for Duchenne muscular dystrophy and age‐related muscle wasting

Zhang

Wang

et al. 2019

J cachexia sarcopenia muscle

View full text Add to dashboard Cite

Background Muscle wasting occurs in response to various physiological and pathological conditions, including ageing and Duchenne muscular dystrophy (DMD). Transforming growth factor‐β1 (TGF‐β1) contributes to muscle pathogenesis in elderly people and DMD patients; inhibition of TGF‐β1 signalling is a promising therapeutic strategy for muscle‐wasting disorders. Hemojuvelin (HJV or Hjv as the murine homologue) is a membrane‐bound protein that is highly expressed in skeletal muscle, heart, and liver. In hepatic cells, Hjv acts as a coreceptor for bone morphogenetic protein, a TGF‐β subfamily member. The aim of this study was to investigate whether Hjv plays an essential role in muscle physiological and pathophysiological processes by acting as a coreceptor for TGF‐β1 signalling. Methods Conventional and conditional Hjv knockout mice as well as mdx and aged mice transfected with Hjv overexpression vector were used to study the role of Hjv in muscle physiology and pathophysiology. qRT‐PCR, western blotting, and immunohistochemistry examinations were conducted to evaluate gene, protein, and structural changes in vivo and in vitro . Exercise endurance was determined using treadmill running test, and muscle force was detected by an isometric transducer. RNA interference, immunoprecipitation, and dual‐luciferase reporter assays were utilized to explore the mechanism by which Hjv regulates TGF‐β1 signalling in skeletal muscle. Results Conventional and conditional Hjv knockout mice displayed muscle atrophy, fibrosis, reduced running endurance, and muscle force. HJV was significantly down‐regulated in the muscles of DMD patients ( n = 3, mean age: 11.7 ± 5.7 years) and mdx mice as well as in those of aged humans ( n = 10, 20% women, mean age: 75.1 ± 9.5 years) and mice. Overexpression of Hjv rescued dystrophic and age‐related muscle wasting. Unlike its function in hepatic cells, the bone morphogenetic protein downstream phosphorylated p‐Smad1/5/8 signalling pathway was unchanged, but TGF‐β1, TGF‐β receptor II (TβRII), and p‐Smad2/3 expression were increased in Hjv‐ deficient muscles. Mechanistically, loss of Hjv promoted activation of Smad3 signalling induced by TGF‐β1, whereas Hjv overexpression inhibited TGF‐β1/Smad3 signalling by directly interacting with TβRII on the muscle membrane. Conclusions Our findings identify an unrecognized role of HJV in skeletal muscle by regulating TGF‐β1/Smad3 signalling as a coreceptor for TβRII. Unlike the TGF‐β1/Smad3 pathway, HJV could be a reliable drug target as its expression is not widespread. Novel therapeutic strategies could potentially be devised to interfere only with the muscle function of HJV to treat DMD and age‐re...

show abstract

“…Intriguingly, combined deficiency of PGC‐1β and PGC‐1α in mice skeletal muscle results in a reduction in muscle oxidative capacity but does not cause glucose intolerance or insulin resistance. Therefore, PGC‐1 coactivators may be dispensable for fundamental fibre‐type determination and insulin sensitivity .…”

Section: Mechanisms Involved In Controlling Myofiber Types During Embmentioning

confidence: 99%

Metabolic control of myofibers: promising therapeutic target for obesity and type 2 diabetes

Duan

Tan

et al. 2017

Obesity Reviews

View full text Add to dashboard Cite

Mammalian skeletal muscles are composed of two major fibre types (I and II) that differ in terms of size, metabolism and contractile properties. In general, slow-twitch type I fibres are rich in mitochondria and have a greater insulin sensitivity than fast-twitch type II skeletal muscles. Although not widely appreciated, a forced induction of the slow skeletal muscle phenotype may inhibit the progress of obesity and diabetes. This potentially forms the basis for targeting slow/oxidative myofibers in the treatment of obesity. In this context, a better understanding of the molecular basis of fibre-type specification and plasticity may help to identify potential therapeutic targets for obesity and diabetes.

show abstract

Total Skeletal Muscle PGC-1 Deficiency Uncouples Mitochondrial Derangements from Fiber Type Determination and Insulin Sensitivity

Cited by 48 publications

References 0 publications

Expression of mitochondrial fission and fusion regulatory proteins in skeletal muscle during chronic use and disuse

Expression of mitochondrial fission and fusion regulatory proteins in skeletal muscle during chronic use and disuse

Hemojuvelin is a novel suppressor for Duchenne muscular dystrophy and age‐related muscle wasting

Metabolic control of myofibers: promising therapeutic target for obesity and type 2 diabetes

Contact Info

Product

Resources

About