Exercise Inducible Lactate Dehydrogenase B Regulates Mitochondrial Function in Skeletal Muscle

Abstract

Edited by Jeffrey PessinLactate 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 exerciseinduced peroxisome proliferator-activated receptor ␥ coactivator 1␣ (PGC-1␣). Ldhb gene promoter reporter studies demonstrated that PGC-1␣ 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.Muscle fitness and resistance to fatigue depend strongly on the capacity to burn the fuels, including fatty acids and glucose, to meet ATP demands (1-5). Exercise training is effective in improving muscle fitness by promoting favorable muscle metabolic reprograming including capacity for fuel burning, mitochondrial ATP production, and contraction (6 -13). Conversely, many chronic diseases, including obesity, diabetes, muscular diseases, and aging, are associated with decreased muscle fitness, contributing to a vicious cycle of inactivity and further promoting the progression of chronic diseases (6 -8, 11, 12, 14). Thus, a better understanding of the molecular regulatory pathways involved in the beneficial effects of exercise training on muscle fuel metabolism could yield novel therapeutic targets aimed at the prevention or treatment of diseases associated with muscle bioenergetics defects.The molecular and cellular mechanisms of skeletal muscle adaptation to exercise training are unclear. Exercise traininginduced adaptations in skeletal muscle are reflected, in part, by changes in transcriptional response and metabolite flux (1,2,4,5,11,15,16). Previous studies have demonstrated that the PGC-1␣ 3 transcriptional regulatory circuit, including the nuclear receptors PPAR and ERR, is a key transducer of exercise-responsive gene expression. The PGC-1␣ circuit regulates a broad array of genes involved in mitochondrial biogenesis and fuel metabolism (17)(18)(19)(20)(21)(22)(23)(24)(25). Evidence is also emerging that manipulation of metabolic enzyme or...

Cell autonomous requirement of Neurofibromin (Nf1) for postnatal muscle hypertrophic growth and metabolic homeostasis

“…Intriguingly, Pdk2, Pdk4 and Ldhb were upregulated. The B-isoform of LDH is mainly expressed in oxidative muscle, and overexpression of Ldhb increases oxidative metabolism [73] in line with the oxidative phenotype we observe. PDK2 and PDK4 negatively regulate Pyruvate dehydrogenase and thus impair funneling Pyruvate from glycolysis towards usage in the TCA cycle, shunting mitochondrial metabolism towards fatty acid usage [13].…”

AMPK activation caused by reduced liver lactate metabolism protects against hepatic steatosis in MCT1 haploinsufficient mice

“…MCT1+/− mice do not show increased hepatic LDHB isoform expression. Interestingly, LDHB induction in muscle was recently correlated with a decrease in pH associated with an increase in intracellular lactate concentration [28] . Thus, an increase in lactate uptake via both MCT1 and MCT2 in hepatocytes with a lowering of intracellular pH could be a trigger for enhanced LDHB expression as observed in muscle [28] .…”

“…Interestingly, LDHB induction in muscle was recently correlated with a decrease in pH associated with an increase in intracellular lactate concentration [28] . Thus, an increase in lactate uptake via both MCT1 and MCT2 in hepatocytes with a lowering of intracellular pH could be a trigger for enhanced LDHB expression as observed in muscle [28] . In our transgenic mouse model, the reduced hepatic MCT1 transporter expression (as well as the lack of enhanced MCT2 expression) could prevent the pH/lactate-dependent induction in LDHB isoform in hepatocytes and the elevated production of pyruvate.…”

Sarcolipin Signaling Promotes Mitochondrial Biogenesis and Oxidative Metabolism in Skeletal Muscle

“…The levels of NADH dehydrogenase subunit 1 (Nd1, mtDNA) were quantified (using qPCR) and normalized to the levels of LPL (genomic DNA) ( Liang et al, 2016 ). The primers were mtDNA Nd1 (mt-Nd1) forward (Fw), 5’-CCCATTCGC GTTATTCTT-3’; mt-Nd1 reverse (Rv), 5’-AAGTTGATCG TAACGGAAGC-3’; LPL Fw, 5’-GGATGGACGGTA AGAGTGATTC-3’; and LPL Rv, 5’-ATCCAAGGGTAGCAGACAGGT-3’.…”