ABSTRACT
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 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.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Adiposity/genetics , Fatty Acids/metabolism , Metabolic Diseases/genetics , Muscle, Skeletal/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Animals , Gene Expression Regulation , Insulin Resistance/genetics , Male , Metabolic Diseases/metabolism , Mice, Inbred C57BL , Mice, Knockout , Obesity/genetics , Obesity/metabolism , Oxidation-Reduction , RNA Interference , Reverse Transcriptase Polymerase Chain Reaction/methods , YAP-Signaling ProteinsABSTRACT
The Yes-associated protein (YAP) is a core effector of the Hippo pathway, which regulates proliferation and apoptosis in organ development. YAP function has been extensively characterized in epithelial cells and tissues, but its function in adult skeletal muscle remains poorly defined. Here we show that YAP positively regulates basal skeletal muscle mass and protein synthesis. Mechanistically, we show that YAP regulates muscle mass via interaction with TEAD transcription factors. Furthermore, YAP abundance and activity in muscles is increased following injury or degeneration of motor nerves, as a process to mitigate neurogenic muscle atrophy. Our findings highlight an essential role for YAP as a positive regulator of skeletal muscle size. Further investigation of interventions that promote YAP activity in skeletal muscle might aid the development of therapeutics to combat muscle wasting and neuromuscular disorders.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Muscle Fibers, Skeletal/metabolism , Muscle Fibers, Skeletal/pathology , Phosphoproteins/metabolism , Protein Serine-Threonine Kinases/metabolism , Signal Transduction , Adaptor Proteins, Signal Transducing/genetics , Animals , Blotting, Western , Cell Cycle Proteins , Denervation , Female , HEK293 Cells , Hippo Signaling Pathway , Humans , Hypertrophy , Male , Mice, Inbred C57BL , Muscular Atrophy/metabolism , Muscular Atrophy/pathology , Nerve Degeneration/pathology , Organ Size , Phosphoproteins/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Transcription Factors/metabolism , Up-Regulation , YAP-Signaling ProteinsABSTRACT
We compared carcass analysis and hydrogen isotope dilution methods to measure total body water (TBW) and body composition in a small altricial carnivore, the mink. Dilution space (D) of mink at 21-42 days of age (n=20), was determined after subcutaneous administration of tritiated water. The same animals were then used to determine TBW and body composition by carcass analysis and to derive predictive empirical relationships between TBW and total body fat, protein and energy. A separate validation set of 27 kits was used to test the accuracy of predicting body composition from TBW. D overestimated TBW by a consistent and predictable 4.1% (R(2)=0.999, P<0.001). Our estimates of fat, protein and energy content, using equations derived from TBW, were not significantly different than those obtained from direct carcass analysis (P>0.980) in either the initial or validation set of mink. TBW was shown to decrease from 81 to 76% and total body protein to increase from 14 to 19% of LBM of the kits from 21 to 42 days of age. Although a rapidly changing hydration state was apparent in neonates, we conclude that when this is taken into account, accurate estimates of body composition can be obtained from hydrogen isotope dilution.
