Stra13 regulates oxidative stress mediated skeletal muscle degeneration

Vercherat, Cécile; Chung, Teng-Kai; Yalçın, Sakine; Gulbagci, Neriman Tuba; Gopinadhan, Suma; Ghaffari, Saghi; Taneja, Reshma

doi:10.1093/hmg/ddp383

Cited by 35 publications

(35 citation statements)

References 45 publications

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“…Although Bhlhe40 can regulate the activation of satellite cells by antagonizing Notch signaling and can protect skeletal muscle from oxidative stress-induced damage by activating the expression of HO-1 (25), its function during exercise has not been examined before. The intracellular signals of exercise are transduced by (i) free Ca 2ϩ ions stimulated signaling pathways, (ii) metabolites, (iii) hypoxia, and (iv) mechanical tension (39).…”

Section: Discussionmentioning

confidence: 99%

“…Bhlhe40 is ubiquitously expressed in most adult tissues but has especially strong expression in skeletal muscle (22,24), where it regulates the activation of myogenic stem cells named satellite cells by antagonizing Notch signaling (24). Besides, Bhlhe40 can protect skeletal muscle from reactive oxidative species (ROS)-induced damage by activating the expression of a key cytoprotective enzyme, heme oxygenase 1 (HO-1) (25).…”

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confidence: 99%

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Bhlhe40 Represses PGC-1α Activity on Metabolic Gene Promoters in Myogenic Cells

Chung

Kao

Villarroya

et al. 2015

Molecular and Cellular Biology

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c PGC-1␣ is a transcriptional coactivator promoting oxidative metabolism in many tissues. Its expression in skeletal muscle (SKM) is induced by hypoxia and reactive oxidative species (ROS) generated during exercise, suggesting that PGC-1␣ might mediate the cross talk between oxidative metabolism and cellular responses to hypoxia and ROS. Here we found that PGC-1␣ directly interacted with Bhlhe40, a basic helix-loop-helix (bHLH) transcriptional repressor induced by hypoxia, and protects SKM from ROS damage, and they cooccupied PGC-1␣-targeted gene promoters/enhancers, which in turn repressed PGC-1␣ transactivational activity. Bhlhe40 repressed PGC-1␣ activity through recruiting histone deacetylases (HDACs) and preventing the relief of PGC-1␣ intramolecular repression caused by its own intrinsic suppressor domain. Knockdown of Bhlhe40 mRNA increased levels of ROS, fatty acid oxidation, mitochondrial DNA, and expression of PGC-1␣ target genes. Similar effects were also observed when the Bhlhe40-mediated repression was rescued by a dominantly active form of the PGC-1␣-interacting domain (PID) from Bhlhe40. We further found that Bhlhe40-mediated repression can be largely relieved by exercise, in which its recruitment to PGC-1␣-targeted cis elements was significantly reduced. These observations suggest that Bhlhe40 is a novel regulator of PGC-1␣ activity repressing oxidative metabolism gene expression and mitochondrion biogenesis in sedentary SKM. Skeletal muscle (SKM) is one of the major metabolic organs, and it has the ability to adapt to various physiological conditions, such as cold, exercise, and sedentary life, by adjusting the balance between glycolytic and oxidative metabolism to meet the energy requirement under these conditions (1). Recent studies suggest that this adaptation relies much on the expression and activity of PGC-1␣, a transcriptional coactivator highly expressed in tissues with high energy metabolism (1, 2). PGC-1␣ enhances the activity of many nuclear receptors (NR), including peroxisome proliferator-activated receptor ␥ (PPAR␥), estrogen receptor (ER), and glucocorticoid receptor (GR), and non-NR transcription factors, such as MEF2, Sox9, FoxO1, and SREBP1 (reviewed in reference 3 and references therein), to promote oxidative metabolism, metabolic thermogenesis adaptation, biogenesis of mitochondria, gluconeogenesis, and fatty acid oxidation in various tissues (4-6). Overexpression of PGC-1␣ can promote metabolic switch from anaerobic glycolysis to oxidative metabolism (7,8). Current studies also show that PGC-1␣ plays critical roles in orchestrating the cellular response to hypoxia (9).In SKM, PGC-1␣ is preferentially expressed in oxidative metabolism-dependent slow-twitch fibers (10), and its overexpression can convert putative fast-twitch fibers into slow-twitch fibers (10). The activation of oxidative and slow-twitch muscle-specific genes by PGC-1␣ is mediated through its coactivation of Mef2 and PPAR binding to the upstream regulatory sites of these target genes (11). PGC-1␣ null mice sho...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Bhlhe40 Represses PGC-1α Activity on Metabolic Gene Promoters in Myogenic Cells

Chung

Kao

Villarroya

et al. 2015

Molecular and Cellular Biology

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“…This is associated with a defect in the size and branching of the differentiated myotubes (23). At the regulatory levels, it was shown that the transcriptional repressor Stra13, which is elevated in dystrophin-deficient mdx mice, protects MuSCs from oxidative damage whereas Stra13 deficiency exacerbates muscular dystrophy (340).…”

Section: Muscular Dystrophiesmentioning

confidence: 99%

Redox Control of Skeletal Muscle Regeneration

Moal

Pialoux

Juban

et al. 2017

Antioxidants & Redox Signaling

152

120

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Skeletal muscle shows high plasticity in response to external demand. Moreover, adult skeletal muscle is capable of complete regeneration after injury, due to the properties of muscle stem cells (MuSCs), the satellite cells, which follow a tightly regulated myogenic program to generate both new myofibers and new MuSCs for further needs. Although reactive oxygen species (ROS) and reactive nitrogen species (RNS) have long been associated with skeletal muscle physiology, their implication in the cell and molecular processes at work during muscle regeneration is more recent. This review focuses on redox regulation during skeletal muscle regeneration. An overview of the basics of ROS/RNS and antioxidant chemistry and biology occurring in skeletal muscle is first provided. Then, the comprehensive knowledge on redox regulation of MuSCs and their surrounding cell partners (macrophages, endothelial cells) during skeletal muscle regeneration is presented in normal muscle and in specific physiological (exercise-induced muscle damage, aging) and pathological (muscular dystrophies) contexts. Recent advances in the comprehension of these processes has led to the development of therapeutic assays using antioxidant supplementation, which result in inconsistent efficiency, underlying the need for new tools that are aimed at precisely deciphering and targeting ROS networks. This review should provide an overall insight of the redox regulation of skeletal muscle regeneration while highlighting the limits of the use of nonspecific antioxidants to improve muscle function. Antioxid. Redox Signal. 27, 276-310.

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“…Dystrophin-deficient muscles are highly susceptible to the oxidative stress that results from the early onset of muscle degeneration. Muscle necrosis actively occurs following the degeneration, leading to fibrosis and calcification of muscle fibers (Vercherat et al, 2009). It has been suggested that vascular calcification is actively regulated by osteogenic gene expression in vascular smooth muscle cells (Giachelli, 1999).…”

Section: Mechanisms Of Calcificationmentioning

confidence: 99%