Next Generation Mendelian Genetics: Muscle Hypertrophy
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ABSTRACT: The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases. Samples were collected from a single, multi-generational family with the same phenotype of exaggerated muscular development (muscular hypertrophy) and strength characterized by reduced fat pad thickness under the skin. All family members deny "body building" activities, and are so far negative for known gene mutation that have been identified as associated with excessive muscle development. All family members have examples of demonstrating extraordinary strength occurring both in childhood and old age. No negative associated phenotype traits with the muscle hypertrophy phenotype have been identified.
SECONDARY ACCESSION(S): PRJNA174118PRJNA174117
REPOSITORIES: dbGaP
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Project description:<p>The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases.</p> <p>Samples were collected from a single, multi-generational family with the same phenotype of exaggerated muscular development (muscular hypertrophy) and strength characterized by reduced fat pad thickness under the skin. All family members deny "body building" activities, and are so far negative for known gene mutation that have been identified as associated with excessive muscle development. All family members have examples of demonstrating extraordinary strength occurring both in childhood and old age. No negative associated phenotype traits with the muscle hypertrophy phenotype have been identified.</p>
| phs000541.v1.p1 | EGA
Project description:Skeletal muscle wasting results from numerous pathological conditions impacting both the musculoskeletal and nervous systems. A unifying feature of these pathologies is the upregulation of members of the E3 ubiquitin ligase family, resulting in increased proteolytic degradation of target proteins. Despite the critical role E3 ubiquitin ligases in regulating muscle mass, the specific proteins they target for degradation and the mechanisms by which they regulate skeletal muscle homeostasis remain ill-defined. Here, using zebrafish loss of function models combined with in vivo cell biology and proteomic approaches, we identified the endoplasmic reticulum chaperone, BiP, as a novel target of the E3 ubiquitin ligase atrogin-1. A loss in atrogin-1 results in an accumulation of BiP, leading to impaired mitochondrial dynamics and a subsequent loss in muscle fibre integrity. We further implicate a disruption in atrogin-1 mediated BiP regulation in the pathogenesis of Duchenne Muscular Dystrophy. We reveal that BiP is not only upregulated in Duchenne Muscular Dystrophy, but its inhibition using pharmacological strategies, or by upregulating atrogin-1, significantly ameliorates pathology in a zebrafish model of Duchenne Muscular Dystrophy. Collectively, our data implicates a novel disease axis in the pathogenesis of Duchenne Muscular Dystrophy, and highlights atrogin-1’s essential role in maintaining muscle homeostasis.
2024-03-07 | PXD038406 | Pride
Project description:In response to skeletal muscle injury, adult myogenic stem cells, known as satellite cells, are activated and undergo proliferation and differentiation to regenerate new muscle fibers. The skeletal muscle-specific microRNA, miR-206, is up-regulated in satellite cells following muscle injury, but its role in muscle regeneration has not been defined. Here we show that skeletal muscle regeneration in response to cardiotoxin injury is impaired in mice lacking miR-206. Loss of miR-206 also accelerates and exacerbates the dystrophic phenotype of mdx mice, a model for Duchenne muscular dystrophy. MiR-206 promotes satellite cell differentiation and fusion to form multinucleated myofibers by suppressing a collection of negative regulators of myogenesis. Our findings reveal an essential role for miR-206 in satellite cell differentiation during skeletal muscle regeneration and as a modulator of Duchenne muscular dystrophy. total RNA obtained from TA muscle of mdx and 3 miR-206 KO; mdx mice at 3 months of age.
2012-04-30 | E-GEOD-36077 | biostudies-arrayexpress
Project description:Dysfunction of the dystrophin-glycoprotein complex (DGC) is a frequent cause of hereditary forms of muscular dystrophy. Although DGC function in maintaining skeletal muscle integrity has been well characterized, little is known about how the DGC complex is coordinately regulated at the transcriptional level. To test this hypothesis, we engineered HDAC4 stably overexpressing and control myotubes in an in vitro model of muscle differentiation. Here we present evidence that HDAC4, a neural activity-responsive histone deacetylase, is a critical transcriptional regulator of the DGC complex. We show that HDAC4 can repress multiple components of the DGC complex, including dystrophin and sarcoglycan family members in both cultured myotubes. To confirm this finding, the protein levels of core DGC complex members including dystrophin, sarcoglycan complex members, and additional dystrophin-associated proteins were evaluated in differentiated myotubes by western analysis. Keywords: genetic modification and cell type comparison of muscle cells
2008-03-25 | GSE10678 | GEO
Project description:In response to skeletal muscle injury, adult myogenic stem cells, known as satellite cells, are activated and undergo proliferation and differentiation to regenerate new muscle fibers. The skeletal muscle-specific microRNA, miR-206, is up-regulated in satellite cells following muscle injury, but its role in muscle regeneration has not been defined. Here we show that skeletal muscle regeneration in response to cardiotoxin injury is impaired in mice lacking miR-206. Loss of miR-206 also accelerates and exacerbates the dystrophic phenotype of mdx mice, a model for Duchenne muscular dystrophy. MiR-206 promotes satellite cell differentiation and fusion to form multinucleated myofibers by suppressing a collection of negative regulators of myogenesis. Our findings reveal an essential role for miR-206 in satellite cell differentiation during skeletal muscle regeneration and as a modulator of Duchenne muscular dystrophy.
2012-05-01 | GSE36077 | GEO
Project description:Decline in skeletal muscle mass and lower muscular strength are prognostic factors in advanced human cancers. We found that breast cancer suppressed O-linked N-acetylglucosamine (O-GlcNAc) protein modification in skeletal muscle through extracellular-vesicle-encapsulated miR-122 that targeted O-GlcNAc transferase (OGT). Specifically, O-GlcNAcylation of ryanodine receptor 1 (RYR1) Ca2+ release channel competed with NEK10-mediated phosphorylation and increased K48-linked ubiquitination and proteasomal degradation, whereas O-GlcNAcylation of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA3) increased K63-linked ubiquitination and elevated protein level. Muscular protein O-GlcNAcylation was regulated by hypoxia and lactate through HIF1A-dependent OGT promoter activation, and elevated after exercise. Suppressed O-GlcNAcylation in the setting of cancer, especially through increased RYR1 protein, led to Ca2+ leak and calpain protease activation to trigger myofibrillar protein cleavage. This was associated with reduced skeletal muscle mass and contractility in tumor-bearing mice. Our findings link O-GlcNAcylation to muscular protein homeostasis and contractility, and reveal a mechanism of cancer-associated muscle dysregulation.
2023-03-10 | PXD021232 | Pride
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:Dysfunction of the dystrophin-glycoprotein complex (DGC) is a frequent cause of hereditary forms of muscular dystrophy. Although DGC function in maintaining skeletal muscle integrity has been well characterized, little is known about how the DGC complex is coordinately regulated at the transcriptional level. To test this hypothesis, we engineered HDAC4 stably overexpressing and control myotubes in an in vitro model of muscle differentiation. Here we present evidence that HDAC4, a neural activity-responsive histone deacetylase, is a critical transcriptional regulator of the DGC complex. We show that HDAC4 can repress multiple components of the DGC complex, including dystrophin and sarcoglycan family members in both cultured myotubes. To confirm this finding, the protein levels of core DGC complex members including dystrophin, sarcoglycan complex members, and additional dystrophin-associated proteins were evaluated in differentiated myotubes by western analysis. C2C12 mouse myotubes were infected with either a HDAC4 expressing or control (Neo) retroviruses. After stable selection, myotubes were differentiated at 90% confluency in 2% horse serum (Hyclone) for 4 days. At this time point, RNA was extracted and the two types of cells compared in a microarray analysis.
2010-05-25 | E-GEOD-10678 | biostudies-arrayexpress
Project description:Cancer is considered as a disease of a specific organ, but its effects are felt throughout the body. The systemic effects of cancer can lead to weakness in muscles and heart, which hastens cancer-associated death. miR-486 is a myogenic microRNA and its reduced expression in skeletal muscle is observed in muscular dystrophy. Muscle-specific transgenic expression of miR-486 using muscle creatine kinase promoter (MCK-miR-486) partially rescues skeletal muscle defects in muscular dystrophy animal models. We had previously demonstrated reduced circulating and skeletal muscle levels of miR-486 in several cancer types and lower miR-486 levels correlated with skeletal muscle defects and functional limitations in mammary tumor models. Therefore, skeletal muscle defects induced by cancer could resemble defects observed in various dystrophies, which could be reversed through skeletal muscle expression of miR-486. We performed functional limitations studies and biochemical analysis of skeletal muscles of MMTV-Neu transgenic mice that mimic HER2+ breast cancer and MMTV-PyMT transgenic mice that mimic luminal subtype B breast cancer and these mice crossed to MCK-miR-486 transgenic mice. miR-486 significantly prevented tumor-induced reduction in muscle contraction force, grip strength, and rotarod performance in MMTV-Neu, but not in MMTV-PyMT mice. In MMTV-Neu model, miR-486 reversed several of the cancer-induced changes in skeletal muscle including loss of p53, phospho-AKT, and phospho-laminin alpha 2 (LAMA2) and gain of phosphorylation of the pre-mRNA processing factor hnRNPA0 and the splicing factor SRSF10. LAMA2 is a part of the dystrophin-associated glycoprotein complex, and its loss-of-function mutation is associated with congenital muscular dystrophy. Thus, similar to muscular dystrophy, miR-486 has the potential to reverse skeletal muscle defects and cancer burden in select cancer types.
2022-05-19 | PXD028554 | Pride
Project description:Excessive or sustained glucocorticoid (GC) exposure causes muscle wasting. Paradoxically, moderate or transient GC exposure elicits ergogenic effects, evidenced by their widespread use as doping agents by endurance athletes and poorly understood efficacy in Duchenne muscular dystrophy (DMD), a genetic muscle wasting disease. While mechanisms underlying GC-mediated muscle wasting are well defined, the molecular basis for the latter remains unknown. In this arm of our studies, we compare expression profiles in quadriceps tissue from KLF15 transgenic (MTg) and non-Tg mice.
2015-12-01 | GSE74623 | GEO