title: Exercise Inducible Lactate Dehydrogenase B Regulates Mitochondrial Function in Skeletal Muscle.
abstract: Lactate dehydrogenase (LDH) catalyzes the interconversion of pyruvate and lactate, which are critical fuel metabolites of skeletal muscle particularly during exercise. However, the physiological relevance of LDH remains poorly understood. Here we show that Ldhb expression is induced by exercise in human muscle and negatively correlated with changes in intramuscular pH levels, a marker of lactate production, during isometric exercise. We found that the expression of Ldhb is regulated by exercise-induced peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Ldhb gene promoter reporter studies demonstrated that PGC-1α activates Ldhb gene expression through multiple conserved estrogen-related receptor (ERR) and myocyte enhancer factor 2 (MEF2) binding sites. Transgenic mice overexpressing Ldhb in muscle (muscle creatine kinase (MCK)-Ldhb) exhibited increased exercise performance and enhanced oxygen consumption during exercise. MCK-Ldhb muscle was shown to have enhanced mitochondrial enzyme activity and increased mitochondrial gene expression, suggesting an adaptive oxidative muscle transformation. In addition, mitochondrial respiration capacity was increased and lactate production decreased in MCK-Ldhb skeletal myotubes in culture. Together, these results identified a previously unrecognized Ldhb-driven alteration in muscle mitochondrial function and suggested a mechanism for the adaptive metabolic response induced by exercise training.
authors.affiliation: From the State Key Laboratory of Pharmaceutical Biotechnology and Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing 210061, China.
authors.forename: Xijun
authors.initials: X
authors.lastname: Liang
authors.affiliation: From the State Key Laboratory of Pharmaceutical Biotechnology and Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing 210061, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.affiliation: From the State Key Laboratory of Pharmaceutical Biotechnology and Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing 210061, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Fu
authors.affiliation: From the State Key Laboratory of Pharmaceutical Biotechnology and Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing 210061, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: From the State Key Laboratory of Pharmaceutical Biotechnology and Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing 210061, China.
authors.forename: Danxia
authors.initials: D
authors.lastname: Zhou
authors.affiliation: From the State Key Laboratory of Pharmaceutical Biotechnology and Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing 210061, China.
authors.forename: Liwei
authors.initials: L
authors.lastname: Xiao
authors.affiliation: From the State Key Laboratory of Pharmaceutical Biotechnology and Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing 210061, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: the Department of Biochemistry and Molecular Biology, School of Medicine, Southeast University, Nanjing 210009, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Kong
authors.affiliation: the Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, Florida 32804.
authors.forename: Hui
authors.initials: H
authors.lastname: Xie
authors.affiliation: the Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, Florida 32804.
authors.forename: Fanchao
authors.initials: F
authors.lastname: Yi
authors.affiliation: the Diabetes and Obesity Research Center, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827, and.
authors.forename: Ling
authors.initials: L
authors.lastname: Lai
authors.affiliation: the Diabetes and Obesity Research Center, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827, and.
authors.forename: Rick B
authors.initials: RB
authors.lastname: Vega
authors.affiliation: the Diabetes and Obesity Research Center, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827, and.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Kelly
authors.affiliation: the Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, Florida 32804.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Smith
authors.affiliation: From the State Key Laboratory of Pharmaceutical Biotechnology and Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing 210061, China, ganzj@nju.edu.cn.|the Collaborative Innovation Center of Genetics and Development, Shanghai 200438, China.
authors.forename: Zhenji
authors.initials: Z
authors.lastname: Gan
mesh_terms: D000818:Animals; D052283:Creatine Kinase, MM Form / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D007770:L-Lactate Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008931:Mitochondria, Muscle / Q000201:enzymology* / Q000235:genetics; D018482:Muscle, Skeletal / Q000201:enzymology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism; D010805:Physical Conditioning, Animal
chemical_list: D007527:Isoenzymes; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D007770:L-Lactate Dehydrogenase; C409667:lactate dehydrogenase 1; D052283:Creatine Kinase, MM Form
keywords: bioenergetics; exercise; gene regulation; mitochondria; skeletal muscle