HDAC11 is a novel regulator of fatty acid oxidative metabolism in skeletal muscle

Abstract

Skeletal muscle is the largest tissue in mammalian organisms and is a key determinant of basal metabolic rate and whole‐body energy metabolism. Histone deacetylase 11 (HDAC11) is the only member of the class IV subfamily of HDACs, and it is highly expressed in skeletal muscle, but its role in skeletal muscle physiology has never been investigated. Here, we describe for the first time the consequences of HDAC11 genetic deficiency in skeletal muscle, which results in the improvement of muscle function enhancing fatigue resistance and muscle strength. Loss of HDAC11 had no obvious impact on skeletal muscle structure but increased the number of oxidative myofibers by promoting a glycolytic‐to‐oxidative muscle fiber switch. Unexpectedly, HDAC11 was localized in muscle mitochondria and its deficiency enhanced mitochondrial content. In particular, we showed that HDAC11 depletion increased mitochondrial fatty acid β‐oxidation through activating the AMP‐activated protein kinase‐acetyl‐CoA carboxylase pathway and reducing acylcarnitine levels in vivo, thus providing a mechanistic explanation for the improved muscle strength and fatigue resistance. Overall, our data reveal a unique role of HDAC11 in the maintenance of muscle fiber‐type balance and the mitochondrial lipid oxidation. These findings shed light on the mechanisms governing muscle metabolism and may have implications for chronic muscle metabolic disease management.

Molecular Characterization and Clinical Relevance of Lysine Acetylation Regulators in Urological Cancers

“…Histone deacetylase11 (HDAC11), one member of the KDACs family, is associated with condensed chromatin structures that in turn suppress transcription. HDAC11 were significantly up-regulated in 6 urological tumors, GSEA analysis found that dysregulation of HDAC11 was involved in cell cycle and oxidative phosphorylation pathways, which was consistent with hallmarks of acetylation regulators and other studies (33)(34)(35). Our immunohistochemistry analysis also validated that cell cycle pathway (CDK2 and CCNA2) was significantly inactivated and oxidative phosphorylation pathway (NDUFB8 and SDHB) was significantly activated, which would may be associated with abnormal expression of acetylation regulators in urological cancers.…”

Mitochondrial Inorganic Polyphosphate (polyP) Is a Potent Regulator of Mammalian Bioenergetics in SH-SY5Y Cells: A Proteomics and Metabolomics Study

“…Moreover, the protective role of creatine in maintaining mitochondrial physiology is also known ( Barbieri et al, 2016 ), and it has been demonstrated that the dietary supplementation with this molecule could improve cellular bioenergetics and mitochondrial function, therefore decreasing neuronal cell death in neurodegeneration ( Adhihetty and Beal, 2008 ; Smith et al, 2014 ). In addition, IPA predicted three upregulated proteins, SIX1, UCP1, and HDAC 11, all of them involved in the upstream regulation of mitochondrial proteins and metabolites, as well as mitochondrial bioenergetics ( Fedorenko et al, 2012 ; Kazak et al, 2015 ; Chowdhury et al, 2017 ; Yang et al, 2017 ; Bhaskara, 2018 ; Hurtado et al, 2021 ). In general, the ‘upstream regulators’ analysis hinted at a cellular compensatory response in MitoPPX cells, in which increased presence of proteins involved in cell stress response, including ATP generation, was present, when compared with the Wt samples.…”

Histone Deacetylases as Modulators of the Crosstalk Between Skeletal Muscle and Other Organs

“…In addition to regulating metabolic homeostasis in the whole body, by controlling insulin sensitivity and glucose tolerance (Bhaskara, 2018), the Class IV member HDAC11 has been recently reported to play a crucial role in skeletal muscle metabolism and function (Hurtado et al, 2021). HDAC11 localizes in muscle mitochondria and its deletion increases mitochondrial content, causing a glycolytic-to-oxidative muscle fiber switch (Hurtado et al, 2021).…”