Yap regulates lipid metabolism in skeletal muscle, and is perturbed by metabolic stress
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE124902 | GEO | 2021/06/27
REPOSITORIES: GEO
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Project description:The Hippo signalling pathway effector Yap positively regulates adult skeletal muscle mass. However, the biological processes that are modulated by Yap in skeletal muscle remain elusive. Using an integrated transcriptomics and proteomics approach, we define the transcriptional programme regulated by Yap in adult skeletal muscle and demonstrate that Yap is a regulator of metabolic substrate utilisation. Inhibition of Yap in mammalian skeletal muscle results in increased, but incomplete, oxidation of fatty acids and features of lipotoxicity. In line with these findings, we demonstrate that Yap abundance is reduced in the skeletal musculature of obese db/db mice, and in muscle biopsies from obese, insulin-resistant humans where YAP levels positively correlate with whole-body metabolic flexibility. Increasing Yap abundance in the striated muscle of db/db mice attenuated the accumulation of fat mass and development of hepatic steatosis. Our findings demonstrate a vital role for Yap in skeletal muscle as a mediator of metabolic substrate utilisation. Modulating Yap activity in skeletal muscle warrants consideration as part of comprehensive approaches to treat metabolic disease.
2021-02-18 | GSE144135 | GEO
Project description:The Hippo signalling pathway effector Yap positively regulates adult skeletal muscle mass. However, the biological processes that are modulated by Yap in skeletal muscle remain elusive. Using an integrated transcriptomics and proteomics approach, we define the transcriptional programme regulated by Yap in adult skeletal muscle and demonstrate that Yap is a regulator of metabolic substrate utilisation. Inhibition of Yap in mammalian skeletal muscle results in increased, but incomplete, oxidation of fatty acids and features of lipotoxicity. In line with these findings, we demonstrate that Yap abundance is reduced in the skeletal musculature of obese db/db mice, and in muscle biopsies from obese, insulin-resistant humans where YAP levels positively correlate with whole-body metabolic flexibility. Increasing Yap abundance in the striated muscle of db/db mice attenuated the accumulation of fat mass and development of hepatic steatosis. Our findings demonstrate a vital role for Yap in skeletal muscle as a mediator of metabolic substrate utilisation. Modulating Yap activity in skeletal muscle warrants consideration as part of comprehensive approaches to treat metabolic disease.
2021-02-18 | GSE144137 | GEO
Project description:Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated ‘omics analysis including proteomics from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.
2021-02-25 | PXD024379 | Pride
Project description:Lipotoxicity, the accumulation of lipids in non-adipose tissues, alters the metabolic transcriptome and mitochondrial metabolism in skeletal muscle. The mechanisms involved remain poorly understood. Here we show that lipotoxicity increased histone deacetylase 4 (HDAC4) and histone deacetylase 5 (HDAC5), which reduced the expression of metabolic genes and oxidative metabolism in skeletal muscle. This metabolic reprogramming was linked with reduced expression of p53-dependent genes that mediate apoptosis and ferroptosis, which preserved cell viability in response to lipotoxicity. Mechanistically, impaired mitochondrial metabolism reduced acetylation of p53 at K120, a modification required for transcriptional activation of apoptosis, while redox drivers of ferroptosis were also reduced. Overexpression of loss-of-function HDAC4 and HDAC5 mutants in skeletal muscle of obese db/db mice enhanced oxidative capacity, increased apoptosis and ferroptosis and reduced muscle mass. This study identifies HDAC4 and HDAC5 as repressors of the oxidative state of skeletal muscle, and that this metabolic reprogramming, considered deleterious for normal metabolism, is critical to preserve muscle integrity in response to lipotoxicity.
2022-10-11 | GSE215185 | GEO
Project description:The Hippo pathway downstream effectors, Yap and Taz, play key roles in cell proliferation and tissue growth, regulating gene expression especially via interaction with Tead transcription factors. To investigate their role in skeletal muscle stem cells, we analysed gene expression changes driven by Taz and compared these to Yap mediated changes to the transcriptome by measurement of gene expression on Affymetrix microarrays. To interrogate overlapping and unique transcriptional changes driven by these Hippo effectors, satellite cell-derived myoblasts were transduced with constitutively active TAZ S89A or YAP S127A retrovirus for 24h or 48h, with empty retrovirus as control. Triplicate microarray analyses of empty vector controls, hYAP1 S127A and TAZ S89A transgenic primary myoblasts were conducted.
2017-06-20 | E-MTAB-5395 | biostudies-arrayexpress
Project description:Vestigial-like (Vgll) proteins are transcriptional co-factors that have been reported to bind Tead family transcription factors to regulate various functions ranging from wing development in the fly to muscle fibre composition and immune function in mice. Here, we characterise Vgll3 in the skeletal muscle lineage. Vgll3 is expressed at low levels in unchallenging muscle but its expression increases in mechanically stimulated and regenerating muscle. VGLL3 is also >3-fold more expressed in the muscles of Duchenne muscular dystrophy patients than in healthy controls and VGLL3 expression is highest in PAX3-FOXO1-associated alveolar rhabdomyosarcoma when compared to other rhabdomyosarcomas, related tumours and adult muscle. Immunoprecipitation of over expressed VGLL3-flag followed by proteomics reveals that VGLL3 binds Tead1,3,4 transcription factors in myoblasts and myotubes. However, unlike Yap, there is no evidence for interaction with a regulatory system such as a kinase cascade. VGLL3 overexpression affects reduces the expression of members of the Hippo negative feedback loop and affects the expression of genes with important functions in muscle or signalling such as Myf5, Pitx2/3 as well as genes that encode Wnt members and IGF-binding proteins. It mainly represses gene expression and regulates similar genes as YAP1 S127A and TAZ S89A but not in a clear agonistic or antagonistic fashion. A loss of Vgll3 almost completely blocks the proliferation of human myoblasts and VGLL3 overexpression promotes myoblasts differentiation. In vivo, the loss of Vgll3 does not prevent normal skeletal muscle development presumably due to feedback signalling and/or redundancy. Collectively, this work identifies Vgll3 as a disease-related transcriptional co-factor that competes with the Hippo effectors Yap and Taz to control myoblast proliferation and differentiation.
2019-06-17 | PXD012040 | Pride
Project description:We address whether the functions of HDAC3 in skeletal muscle require its enzyme activity. By mutating the NCoR/SMRT corepressors in a knock-in mouse model named NS-DADm, we ablated the enzymatic activity of HDAC3 without affecting its protein levels. Compared to the control mice, skeletal muscles from NS-DADm mice showed lower force generation, enhanced fatigue resistance, enhanced fatty acid oxidation, reduced glucose uptake during exercise, upregulated expression of metabolic genes involved in branched-chain amino acids (BCAAs) catabolism, and aging-associated reduction in muscle mass, without changes in the muscle fiber type composition or mitochondrial protein content. These findings demonstrate that the metabolic function of HDAC3 in skeletal muscles requires its enzymatic activity.
2018-11-30 | GSE115226 | GEO
Project description:Skeletal muscles are comprised of gigantic multinucleated cells called muscle fibers, which often span several centimetres in length. Each muscle fiber is densely packed with contractile force-producing myofibrils and ATP-producing mitochondria. During animal development the size of the individual muscle fibers must dramatically increase to match the growth of the animal and to connect growing skeletal elements. How such dramatic tissue growth is coordinated with growth of the contractile apparatus in the muscle fibers is not well understood. Here, we use the large Drosophila flight muscles to mechanistically decipher how muscle fiber growth is controlled during development. We isolated flight muscles from Drosophila melanogaster pupae at 24 h and 32 h APF of the genotypes wt, Dlg5-IR, Slmap-IR, Yorkie-CA, Hippo-IR and isolated total RNA for subsequent BRB-seq sequencing. Our study reveals that regulated activity of core members of the Hippo pathway, Hippo, Warts and Yorkie is required to support post-mitotic flight muscle growth. Interestingly, we identify Dlg5 and Slmap as important members of the STRIPAK phosphatase complex, which negatively regulates Hippo activity and therefore enables post-mitotic muscle growth. Mechanistically, we find that the Hippo pathway controls the timing and the levels of sarcomeric gene expression during muscle development and thus regulates the key components that mediate muscle fiber growth. Since Dlg5, STRIPAK and the Hippo pathway are conserved in mammals a similar mechanism may contribute to skeletal muscle or cardiac growth in humans.
2020-10-03 | GSE158957 | GEO
Project description:Hippo effectors Yap and Taz, Vgll1-4 and Tead 1-4 transcription factors have been linked to satellite cell/ myoblast proliferation and differentiation, muscle function and disease. The molecular function of Vgll3 in skeletal muscle stem cells was investigated using analysis of gene expression by microarrays to determine Vgll3 mediated gene expression changes and compare those to previously determined Taz and Yap mediated changes. Satellite cell-derived myoblasts were transduced with Vgll3 retrovirus for 24h or 48h, with empty retrovirus vector as control. Triplicate microarray analysis of empty vector controls and Vgll3 transgenic primary myoblasts were conducted.
2019-06-17 | E-MTAB-7614 | biostudies-arrayexpress
Project description:Leptin receptors (Lepr) are expressed by various types of stem cells including mesenchymal stem cells, hematopoietic stem cells, embryonic stem cells, and induced pluripotent stem cells. Leptin/lepr signaling is also a central regulator of metabolism. However, the role of Lepr in pluripotency, metabolic disease progression and growth development is still controversial and poorly understood. In the present study, we explored the Lepr function in disease progression, pluripotency and metabolism using day 14.5 mouse embryonic fibroblasts (MEFs) and their reprogrammed induced pluripotent stem cells (iPSCs) as model system. We successfully reprogrammed mouse embryonic fibroblasts into iPSCs from control and db/db (Lepr deficient) mice. Using a global quantitative proteomic approach, we identified key pathways regulating pluripotency, metabolic homeostasis and protein synthesis during fetal growth and development. The Lepr MEFs show abnormal metabolic abnormalities and mitochondrial dysfunction as compared to control MEFs, while Lepr iPSCs show upregulated elongated factor 4 e (eIF4e) protein synthesis pathway and altered Oct4 and Stat3 pathways which are involved in normal fetal growth development. Furthermore, chip analysis revealed that higher Stat3 binding on the promoter of eIF4e in Lepr iPSCs leads to higher protein synthesis in these cell types as compared to control iPSCs. Finally, point mutation corrected Lepr iPSCs using CRISPR/Cas9 gene editing method showed recovered pluripotency, metabolic and protein synthesis pathways. In conclusion, we have shown that Lepr signaling is involved in the regulation of the metabolic properties and key developmental pathways in MEFs and stemness of pluripotent stem cells. Disruption of Lepr signaling has been shown to involve in the pathophysiology of various diseases including obesity and diabetes. The generated MEFs and iPSCs in this present study provide valuable tools to explore the role of Lepr in the progression of obesity, diabetes and metabolic abnormalities, and to find the putative targets of Lepr signaling during the development of these diseases.
2021-09-09 | PXD020959 | Pride