Tbx15 controls skeletal muscle fibre-type determination and muscle metabolism.
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ABSTRACT:
SUBMITTER: Lee KY
PROVIDER: S-EPMC4552045 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Skeletal muscle is composed of both slow-twich oxidative myofibers and fast-twitch glycolytic myofibers that differentially impact muscle metabolism, function, and eventually whole-body physiology. In the present study, we find that the mesodermal transcription factor T-box 15 (Tbx15) is highly and specifically expressed in glycolytic myofibers. Ablation of Tbx15 in vivo leads to a decrease in muscle size due to a decrease in the number of glycolytic fibers, associated with a small increase in the number of oxidative fibers. This shift in fiber composition results in muscles with slower myofiber contraction and relaxation, and also results in decreased whole-body oxygen consumption, decreased spontaneous activity, increased adiposity, and glucose intolerance. In order to identify genes regulated by Tbx15, we utilized C2C12 myoblasts with either a stable retroviral over-expression or stable lentiviral knockdown of Tbx15.
2015-07-03 | GSE70489 | GEO
Project description:Skeletal muscle is composed of both slow-twich oxidative myofibers and fast-twitch glycolytic myofibers that differentially impact muscle metabolism, function, and eventually whole-body physiology. In the present study, we find that the mesodermal transcription factor T-box 15 (Tbx15) is highly and specifically expressed in glycolytic myofibers. Ablation of Tbx15 in vivo leads to a decrease in muscle size due to a decrease in the number of glycolytic fibers, associated with a small increase in the number of oxidative fibers. This shift in fiber composition results in muscles with slower myofiber contraction and relaxation, and also results in decreased whole-body oxygen consumption, decreased spontaneous activity, increased adiposity, and glucose intolerance. In order to identify genes regulated by Tbx15, we utilized C2C12 myoblasts with either a stable retroviral over-expression or stable lentiviral knockdown of Tbx15. RNA was extracted and biotin labelled complementary RNA (cRNA) was prepared from three independent transfections of the four stable C2C12 myoblast cell lines: shTbx15, shGFP, pBABE-Empty-puro, pBABE-Tbx15-puro. Cells were collected at 90% confluency, and subjected to microarray analysis. Affymetrix M430 2.0 Chips were used.
2015-07-03 | E-GEOD-70489 | biostudies-arrayexpress
Project description:Obestatin/GPR39 signaling stimulates skeletal muscle growth and repair by inducing both G-protein-dependent and -independent mechanisms linking the activated GPR39 receptor with distinct sets of accessory and effector proteins. In this work, we describe a new level of activity where obestatin signaling plays a role in the formation, contractile properties and metabolic profile of skeletal muscle through determination of oxidative fiber type. Our data indicate that obestatin regulates Mef2 activity and PGC-1? expression. Both mechanisms result in a shift in muscle metabolism and function. The increase in Mef2 and PGC-1? signaling activates oxidative capacity, whereas Akt/mTOR signaling positively regulates myofiber growth. Taken together, these data indicate that the obestatin signaling acts on muscle fiber-type program in skeletal muscle.
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Project description:Brown adipose tissue (BAT) is an energy-dispensing thermogenic tissue that plays an important role in balancing energy metabolism. Lineage-tracing experiments indicate that brown adipocytes are derived from myogenic progenitors during embryonic development. However, adult skeletal muscle stem cells (satellite cells) have long been considered uniformly determined toward the myogenic lineage. Here, we report that adult satellite cells give rise to brown adipocytes and that microRNA-133 regulates the choice between myogenic and brown adipose determination by targeting the 3'UTR of Prdm16. Antagonism of microRNA-133 during muscle regeneration increases uncoupled respiration, glucose uptake, and thermogenesis in local treated muscle and augments whole-body energy expenditure, improves glucose tolerance, and impedes the development of diet-induced obesity. Finally, we demonstrate that miR-133 levels are downregulated in mice exposed to cold, resulting in de novo generation of satellite cell-derived brown adipocytes. Therefore, microRNA-133 represents an important therapeutic target for the treatment of obesity.
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Project description:Skeletal muscle fibre size is highly variable, and while diffusion appears to limit maximal fibre size, there is no paradigm for the control of minimal size. The optimal fibre size hypothesis posits that the reduced surface area to volume in larger fibres reduces the metabolic cost of maintaining the membrane potential, and so fibres attain an optimal size that minimizes metabolic cost while avoiding diffusion limitation. Here we examine changes during hypertrophic fibre growth in metabolic cost and activity of the Na?-K?-ATPase in white skeletal muscle from crustaceans and fishes. We provide evidence for a major tenet of the optimal fibre size hypothesis by demonstrating that larger fibres are metabolically cheaper to maintain, and the cost of maintaining the membrane potential is proportional to fibre surface area to volume. The influence of surface area to volume on metabolic cost is apparent during growth in 16 species spanning a 20-fold range in fibre size, suggesting that this principle may apply widely.
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Project description:BackgroundSkeletal muscle as a metabolic consumer determines systemic energy homeostasis by regulating myofibre type conversion and muscle mass control. Perturbation of the skeletal muscle metabolism elevates the risk of a variety of diseases including metabolic disorders. However, the regulatory pathways and molecules are not completely understood. The discovery of relevant responsible molecules and the associated network could be an attractive strategy to overcome diseases associated with muscle problems.MethodsAn initial screening using quantitative trait locus analysis enabled us to extract a set of genes including ubiquitin-specific proteases21 (USP21) (r = 0.738; P = 0.004) as potential targets associated with fasting blood glucose content. Given tight regulation of the ubiquitination status of proteins in muscle, we focused on USP21 and generated whole-body (KO) and skeletal muscle-specific USP21 knockout (MKO) mice. Transcriptomics, proteomics, and lipidomics assays in combination with various in vivo and in vitro experiments were performed to understand the functions of USP21 and underlying mechanisms. A high-fat diet (60%)-fed mouse model and diabetic patient-derived samples were utilized to assess the effects of USP21 on energy metabolism in skeletal muscle.ResultsUSP21 was highly expressed in both human and mouse skeletal muscle, and controlled skeletal muscle oxidative capacity and fuel consumption. USP21-KO or USP21-MKO significantly promoted oxidative fibre type changes (Δ36.6% or Δ47.2%), muscle mass increase (Δ13.8% to Δ22.8%), and energy expenditure through mitochondrial biogenesis, fatty acid oxidation, and UCP2/3 induction (P < 0.05 or P < 0.01). Consistently, cold exposure repressed USP21 expression in mouse skeletal muscle (Δ55.3%), whereas loss of USP21 increased thermogenesis (+1.37°C or +0.84°C; P < 0.01). Mechanistically, USP21 deubiquitinated DNA-PKcs and ACLY, which led to AMPK inhibition. Consequently, USP21 ablation diminished diet-induced obesity (WT vs. USP21-KO, Δ8.02 g, 17.1%, P < 0.01; litter vs. USP21-MKO, Δ3.48 g, 7.7%, P < 0.05) and insulin resistance. These findings were corroborated in a skeletal muscle-specific gene KO mouse model. USP21 was induced in skeletal muscle of a diabetic patient (1.94-fold), which was reciprocally changed to p-AMPK (0.30-fold).ConclusionsThe outcomes of this research provide novel information as to how USP21 in skeletal muscle contributes to systemic energy homeostasis, demonstrating USP21 as a key molecule in the regulation of myofibre type switch, muscle mass control, mitochondrial function, and heat generation and, thus, implicating the potential of this molecule and its downstream substrates network as targets for the treatment and/or prevention of muscle dysfunction and the associated metabolic diseases.
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