Testis-Specific Lactate Dehydrogenase (LDH-C4) in Skeletal Muscle Enhances a Pika's Sprint-Running Capacity in Hypoxic Environment.

Yang Wang,Lian Wei,Dengbang Wei,Lina Xu,Linna Wei,Xiao Li

doi:10.3390/ijerph120809218

Yang Wang, Lian Wei + Show 4 more

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https://doi.org/10.3390/ijerph120809218

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Abstract

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.

Highlights

At more than 3000 m above sea level on average, the Qinghai-Tibet Plateau is the highest and largest plateau in the world and possesses a unique environment of nature and geography
Our results indicate the lactate dehydrogenase (LDH)-A4 and LDH-B4 inhibition by N-propyl oxamate is five and two times higher than that of N-isopropyl oxamate, but the Ki of LDH-C4 by the two inhibitors was almost the same
When carbonyl cyanide mchlorophenylhydrazone (CCCP) and NaCN was applied to suppress the oxidative phosphorylation in mitochondria, the vigorous motility of sperm was maintained and the amount of Adenosine Triphosphate (ATP) was kept at the equivalent level to that without CCCP [56,58]. These results suggest that LDH-C4 is the key factor of sperm glycolysis, which has an important role in providing the ATP

Summary

Introduction

At more than 3000 m above sea level on average, the Qinghai-Tibet Plateau is the highest and largest plateau in the world and possesses a unique environment of nature and geography. Hypoxia and cold environment are the most obvious climate characters on the plateau, which expectedly have profound effects on survival. Altitude-related health diseases are important in Qinghai-Tibet since more than nearly. 12 million settle above 2,200 m on the plateau. Every year thousands of people travel from lowland up to the plateau and about 6 million low land immigrants live there permanently. Tibetans have greater hypoxia and hypercapnic ventilatory responsiveness, large lungs, better lung function, and greater lung diffusing capacity than lowlanders [1]. Additional, Tibetans developed only minimal hypoxia pulmonary vasoconstriction [2] and have higher levels of exhaled nitric oxide [3]

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