Class IIa HDACs inhibit cell death pathways and protect muscle integrity in response to lipotoxicity.

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, resulting in increased non-oxidative glucose metabolism. This metabolic reprogramming was also associated with impaired apoptosis and ferroptosis responses, and preserved muscle cell viability in response to lipotoxicity. Mechanistically, increased HDAC4 and 5 decreased acetylation of p53 at K120, a modification required for transcriptional activation of apoptosis. Redox drivers of ferroptosis derived from oxidative metabolism were also reduced. The relevance of this pathway was demonstrated by overexpression of loss-of-function HDAC4 and HDAC5 mutants in skeletal muscle of obese db/db mice, which enhanced oxidative metabolic capacity, increased apoptosis and ferroptosis and reduced muscle mass. This study identifies HDAC4 and HDAC5 as repressors of skeletal muscle oxidative metabolism, which is linked to inhibition of cell death pathways and preservation of muscle integrity in response to lipotoxicity.

Live Metabolic Profile Analysis of Zebrafish Embryos Using a Seahorse XF 24 Extracellular Flux Analyzer.

The Agilent Seahorse Extracellular Flux Analyzer can be used to measure the oxygen consumption rate (OCR) and extra cellular acidification rate (ECAR), from which mitochondrial bioenergetics measurements can be determined including basal respiration, respiration due to ATP turnover, uncoupled respiration/proton leak, and maximum respiration. This novel method demonstrates how to use a Seahorse XF 24 Extracellular Flux Analyzer to measure the bioenergetic flux of zebrafish embryos in vivo during development. This provides a tool that enables characterization of metabolic parameters in a living organism, utilizing Agilent Islet Capture Microplates where respiration parameters can be compared between controls and genetically altered/pharmacologically treated embryos in real time. This method can be used to analyze and identify novel pharmaceuticals and genes that influence respiration, mitochondrial function, and metabolism.

Disruption of the Class IIa HDAC Corepressor Complex Increases Energy Expenditure and Lipid Oxidation.

Drugs that recapitulate aspects of the exercise adaptive response have the potential to provide better treatment for diseases associated with physical inactivity. We previously observed reduced skeletal muscle class IIa HDAC (histone deacetylase) transcriptional repressive activity during exercise. Here, we find that exercise-like adaptations are induced by skeletal muscle expression of class IIa HDAC mutants that cannot form a corepressor complex. Adaptations include increased metabolic gene expression, mitochondrial capacity, and lipid oxidation. An existing HDAC inhibitor, Scriptaid, had similar phenotypic effects through disruption of the class IIa HDAC corepressor complex. Acute Scriptaid administration to mice increased the expression of metabolic genes, which required an intact class IIa HDAC corepressor complex. Chronic Scriptaid administration increased exercise capacity, whole-body energy expenditure and lipid oxidation, and reduced fasting blood lipids and glucose. Therefore, compounds that disrupt class IIa HDAC function could be used to enhance metabolic health in chronic diseases driven by physical inactivity.