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Skeletal muscle PGC-1? controls whole-body lactate homeostasis through estrogen-related receptor ?-dependent activation of LDH B and repression of LDH A.

ABSTRACT: The peroxisome proliferator-activated receptor-? coactivator 1? (PGC-1?) controls metabolic adaptations. We now show that PGC-1? in skeletal muscle drives the expression of lactate dehydrogenase (LDH) B in an estrogen-related receptor-?-dependent manner. Concomitantly, PGC-1? reduces the expression of LDH A and one of its regulators, the transcription factor myelocytomatosis oncogene. PGC-1? thereby coordinately alters the composition of the LDH complex and prevents the increase in blood lactate during exercise. Our results show how PGC-1? actively coordinates lactate homeostasis and provide a unique molecular explanation for PGC-1?-mediated muscle adaptations to training that ultimately enhance exercise performance and improve metabolic health.

SUBMITTER: Summermatter S

PROVIDER: S-EPMC3666691 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Skeletal muscle PGC-1α controls whole-body lactate homeostasis through estrogen-related receptor α-dependent activation of LDH B and repression of LDH A.

Summermatter Serge S Santos Gesa G Pérez-Schindler Joaquín J Handschin Christoph C

Proceedings of the National Academy of Sciences of the United States of America 20130506 21

The peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) controls metabolic adaptations. We now show that PGC-1α in skeletal muscle drives the expression of lactate dehydrogenase (LDH) B in an estrogen-related receptor-α-dependent manner. Concomitantly, PGC-1α reduces the expression of LDH A and one of its regulators, the transcription factor myelocytomatosis oncogene. PGC-1α thereby coordinately alters the composition of the LDH complex and prevents the increase in blood lactate ...[more]

PMID: 23650363

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Project description:LDH-C4 is a lactate dehydrogenase that catalyzes the conversion of pyruvate to lactate. In mammals, ldh-c was originally thought to be expressed only in testis and spermatozoa. Plateau pika (Ochotona curzoniae), which belongs to the genus Ochotona of the Ochotonidea family, is a hypoxia tolerant mammal living 3000-5000 m above sea level on the Qinghai-Tibet Plateau, an environment which is strongly hypoxic. Ldh-c is expressed not only in testis and sperm but also in somatic tissues of plateau pika. In this study, the effects of N-propyl oxamate and N-isopropyl oxamate on LDH isozyme kinetics were compared to screens for a selective inhibitor of LDH-C4. To reveal the role and physiological mechanism of LDH-C4 in skeletal muscle of plateau pika, we investigated the effect of N-isopropyl oxamate on the pika exercise tolerance as well as the physiological mechanism. Our results show that Ki of N-propyl oxamate and N-isopropyl oxamate for LDH-A4, LDH-B4, and LDH-C4 were 0.094 mmol/L and 0.462 mmol/L, 0.119 mmol/L and 0.248 mmol/L, and 0.015 mmol/L and 0.013 mmol/L, respectively. N-isopropyl oxamate is a powerful selective inhibitor of plateau pika LDH-C4. In our exercise tolerance experiment, groups treated with inhibitors had significantly lower swimming times than the uninhibited control group. The inhibition rates of LDH, LD, and ATP were 37.12%, 66.27%, and 32.42%, respectively. Our results suggested that ldh-c is expressed in the skeletal muscle of plateau pika, and at least 32.42% of ATP in the skeletal muscle is catalyzed by LDH-C4 by anaerobic glycolysis. This suggests that pika has reduced dependence on oxygen and enhanced adaptation to hypoxic environment due to increased anaerobic glycolysis by LDH-C4 in skeletal muscle. LDH-C4 in plateau pika plays the crucial role in anaerobic glycolysis and generates ATP rapidly since this is the role of LDH-A4 in most species on plain land, which provide evidence that the native humans and animals in Qinghai-Tibet plateau can adapt to the hypoxia environment.

Project description:Mood instability, a subjective emotional state defined as rapid mood oscillations of up and down, is a symptom that occurs in several psychiatric disorders, particularly major depressive disorder and bipolar disorder. Heat shock protein A12A (HSPA12A) shows decreased expression in the brains of schizophrenia patients. However, the causal effects of HSPA12A in any psychiatric disorders are completely unknown. To investigate whether HSPA12A affects mood stability, Hspa12a-knockout mice (Hspa12a-/-) and wild-type (WT) littermates were subjected to tests of open field, forced swimming, elevated plus maze, and sucrose preference. Cerebral lactate levels were measured in cerebrospinal fluid (CSF). Adult hippocampal neurogenesis (AHN) was assessed by BrdU labeling. We found that acute mood stress increased hippocampal HSPA12A expression and CSF lactate levels in mice. However, Hspa12a-/- mice exhibited behaviors of mood instability (anhedonia, lower locomotor activity, antidepression, and anxiety), which were accompanied by impaired AHN, decreased CSF lactate levels, and downregulated hippocampal glycolytic enzyme expression. By contrast, HSPA12A overexpression increased lactate production and glycolytic enzyme expression of primary hippocampal neurons. Intriguingly, lactate administration alleviated the mood instability and AHN impairment in Hspa12a-/- mice. Further analyses revealed that HSPA12A was necessary for sustaining cerebral lactate homeostasis, which could be mediated by inhibiting GSK3β in hippocampal neurons, to maintain AHN and mood stabilization. Taken together, HSPA12A is defined as a novel regulator of mood stability and exerts therapeutic potential for mood disorder. Our findings establish a framework for determining mood disorder and AHN relevance of cerebral lactate homeostasis. HSPA12A is a novel mood stabilizer through inhibiting GSK3β in hippocampal neurons, thereby sustaining glycolysis-generated lactate to maintain cerebral lactate homeostasis, which ultimately leading to maintenance of hippocampal neurogenesis and mood stabilization.

Dataset Information

Skeletal muscle PGC-1? controls whole-body lactate homeostasis through estrogen-related receptor ?-dependent activation of LDH B and repression of LDH A.

Publications

Skeletal muscle PGC-1α controls whole-body lactate homeostasis through estrogen-related receptor α-dependent activation of LDH B and repression of LDH A.

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