title: Dissociation of muscle insulin sensitivity from exercise endurance in mice by HDAC3 depletion.
abstract: Type 2 diabetes and insulin resistance are associated with reduced glucose utilization in the muscle and poor exercise performance. Here we find that depletion of the epigenome modifier histone deacetylase 3 (HDAC3) specifically in skeletal muscle causes severe systemic insulin resistance in mice but markedly enhances endurance and resistance to muscle fatigue, despite reducing muscle force. This seemingly paradoxical phenotype is due to lower glucose utilization and greater lipid oxidation in HDAC3-depleted muscles, a fuel switch caused by the activation of anaplerotic reactions driven by AMP deaminase 3 (Ampd3) and catabolism of branched-chain amino acids. These findings highlight the pivotal role of amino acid catabolism in muscle fatigue and type 2 diabetes pathogenesis. Further, as genome occupancy of HDAC3 in skeletal muscle is controlled by the circadian clock, these results delineate an epigenomic regulatory mechanism through which the circadian clock governs skeletal muscle bioenergetics. These findings suggest that physical exercise at certain times of the day or pharmacological targeting of HDAC3 could potentially be harnessed to alter systemic fuel metabolism and exercise performance.
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Sungguan
authors.initials: S
authors.lastname: Hong
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Fang
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA.
authors.forename: Wenyun
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Physiology and Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Loro
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Manashree
authors.initials: M
authors.lastname: Damle
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.|International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Guolian
authors.initials: G
authors.lastname: Ding
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jager
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA.
authors.forename: Sisi
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Feng
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Chu
authors.affiliation: Proteomics Resource Center, the Rockefeller University, New York, New York, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Dill
authors.affiliation: Proteomics Resource Center, the Rockefeller University, New York, New York, USA.
authors.forename: Henrik
authors.initials: H
authors.lastname: Molina
authors.affiliation: Department of Physiology and Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Tejvir S
authors.initials: TS
authors.lastname: Khurana
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rabinowitz
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Sun
mesh_terms: D000659:AMP Deaminase / Q000378:metabolism; D000597:Amino Acids, Branched-Chain / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001823:Body Composition; D002940:Circadian Rhythm / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism; D044127:Epigenesis, Genetic; D055785:Gene Knockdown Techniques; D015309:Glucose Clamp Technique; D042421:Histone Code / Q000235:genetics; D006655:Histone Deacetylases / Q000235:genetics*; D007333:Insulin Resistance / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics*; D051379:Mice; D018763:Muscle Fatigue / Q000235:genetics*; D053580:Muscle Strength / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism*; D010805:Physical Conditioning, Animal; D010807:Physical Endurance / Q000235:genetics*; D040901:Proteomics; D060888:Real-Time Polymerase Chain Reaction; D000099186:Histone Deacetylase 3
chemical_list: D000659:AMP Deaminase; D000597:Amino Acids, Branched-Chain; D006655:Histone Deacetylases; D000099186:Histone Deacetylase 3; C579174:AMPD3 protein, mouse