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Tbx15 controls skeletal muscle fibre-type determination and muscle metabolism.

ABSTRACT: Skeletal muscle is composed of both slow-twitch oxidative myofibers and fast-twitch glycolytic myofibers that differentially impact muscle metabolism, function and eventually whole-body physiology. Here we show 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 fibres, associated with a small increase in the number of oxidative fibres. This shift in fibre composition results in muscles with slower myofiber contraction and relaxation, and also decreases whole-body oxygen consumption, reduces spontaneous activity, increases adiposity and glucose intolerance. Mechanistically, ablation of Tbx15 leads to activation of AMPK signalling and a decrease in Igf2 expression. Thus, Tbx15 is one of a limited number of transcription factors to be identified with a critical role in regulating glycolytic fibre identity and muscle metabolism.

SUBMITTER: Lee KY

PROVIDER: S-EPMC4552045 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Tbx15 controls skeletal muscle fibre-type determination and muscle metabolism.

Lee Kevin Y KY Singh Manvendra K MK Ussar Siegfried S Wetzel Petra P Hirshman Michael F MF Goodyear Laurie J LJ Kispert Andreas A Kahn C Ronald CR

Nature communications 20150824

Skeletal muscle is composed of both slow-twitch oxidative myofibers and fast-twitch glycolytic myofibers that differentially impact muscle metabolism, function and eventually whole-body physiology. Here we show 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 fibres, associated with a small increase in the number of oxid ...[more]

PMID: 26299309

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Project description:Fibre type-specific analyses are required for broader understanding of muscle physiology, but such analyses are difficult to conduct due to the extreme time requirements of dissecting and fibre typing individual fibres. Investigations are often confined to a small number of fibres from few participants with low representativeness of the entire fibre population and the participant population. To increase the feasibility of conducting large-scale fibre type-specific studies, a valid and rapid method for high-throughput fibre typing of individually dissected fibres was developed and named THRIFTY (for high-THRoughput Immunofluorescence Fibre TYping). Employing THRIFTY, 400 fibre segments were fixed onto microscope slides with a pre-printed coordinated grid system, probed with antibodies against myosin heavy chain (MyHC)-I and MyHC-II and classified using a fluorescence microscope. The validity and speed of THRIFTY was compared to a previously validated protocol (dot blot) on a fibre-to-fibre basis. Fibre pool purity was evaluated using 'gold standard' SDS-PAGE and silver staining. A modified THRIFTY-protocol using fluorescence western blot equipment was also validated. THRIFTY displayed excellent agreement with the dot blot protocol, κ = 0.955 (95% CI: 0.928, 0.982), P < 0.001. Both the original and modified THRIFTY protocols generated type I and type II fibre pools of absolute purity. Using THRIFTY, 400 fibres were typed just under 11 h, which was approximately 3 times faster than dot blot. THRIFTY is a novel and valid method with high versatility for very rapid fibre typing of individual fibres. THRIFTY can therefore facilitate the generation of large fibre pools for more extensive mechanistic studies into skeletal muscle physiology. KEY POINTS: Skeletal muscle is composed of different fibre types, each with distinct physiological properties. To fully understand how skeletal muscle adapts to external cues such as exercise, nutrition and ageing, fibre type-specific investigations are required. Such investigations are very difficult to conduct due to the extreme time requirements related to classifying individually isolated muscle fibres. To bypass this issue, we have developed a rapid and reliable method named THRIFTY which is cheap as well as versatile and which can easily be implemented in most laboratories. THRIFTY increases the feasibility of conducting larger fibre type-specific studies and enables time-sensitive assays where measurements need to be carried out in close connection with tissue sampling. By using THRIFTY, new insights into fibre type-specific muscle physiology can be gained which may have broad implications in health and disease.

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.

Dataset Information

Tbx15 controls skeletal muscle fibre-type determination and muscle metabolism.

Publications

Tbx15 controls skeletal muscle fibre-type determination and muscle metabolism.

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