Hypoxanthine Induces Muscular ATP Depletion and Fatigue via UCP2.

Cong Yin,Chen Duan,Canjun Zhu,Huihua Zhang,Zewei Ma,Xiaotong Zhu,Qingyan Jiang,Ping Gao,Gang Shu,Fan Li,Yexian Yuan,Lina Wang,Songbo Wang

doi:10.3389/fphys.2021.647743

Cong Yin, Chen Duan + Show 11 more

Open Access

https://doi.org/10.3389/fphys.2021.647743

Copy DOI

Abstract

Hypoxanthine (Hx), an intermediate metabolite of the purine metabolism pathway which is dramatically increased in blood and skeletal muscle during muscle contraction and metabolism, is characterized as a marker of exercise exhaustion. However, the physiological effects of Hx on skeletal muscle remain unknown. Herein, we demonstrate that chronic treatment with Hx through dietary supplementation resulted in skeletal muscle fatigue and impaired the exercise performance of mice without affecting their growth and skeletal muscle development. Hx increased the uncoupling protein 2 (UCP2) expression in the skeletal muscle, which led to decreased energy substrate storage and enhanced glycolysis. These effects could also be verified in acute treatment with Hx through intraperitoneal injection. In addition, muscular specifically knockout of UCP2 through intra-muscle tissue injection of adenovirus-associated virus reversed the effects of Hx. In conclusion, we identified a novel role of Hx in the skeletal muscular fatigue mediated by UCP2-dependent mitochondrial uncoupling. This finding may shed light on the pathological mechanism of clinical muscle dysfunctions due to abnormal metabolism, such as muscle fatigue and weakness.

Highlights

Skeletal muscle, the largest metabolic tissue of the body, is the major source of many metabolites that are released primarily during muscle contraction and in the resting state (Pedersen and Febbraio, 2012; Seiler et al, 2015; Hoffmann and Weigert, 2017)
To investigate the physiological roles of Hx in the skeletal muscle and exercise, mice were treated with Hx through dietary supplement (0, 10, or 20 mg/g in diet)
There was no significant change in 10 mg/g Hx treated group compared to the control, the weight lifting score and grip strength were slightly reduced after treatment with 10 mg/g Hx

Summary

Introduction

The largest metabolic tissue of the body, is the major source of many metabolites that are released primarily during muscle contraction and in the resting state (Pedersen and Febbraio, 2012; Seiler et al, 2015; Hoffmann and Weigert, 2017). These intermediates are characterized as myometabolites because of the important determinant of their levels in the circulation of muscle. Hypoxanthine Induces Muscular Fatigue cause muscle fatigue and soreness These detrimental myometabolites should be paid attention, so that we could fully understand the physiological roles of them

Objectives

Methods

Results

Conclusion