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IRF4 in Skeletal Muscle Regulates Exercise Capacity via PTG/Glycogen Pathway.

ABSTRACT: Exercise-induced fatigue and exhaustion are interesting areas for many researchers. Muscle glycogen is critical for physical performance. However, how glycogen metabolism is manipulated during exercise is not very clear. The aim here is to assess the impact of interferon regulatory factor 4 (IRF4) on skeletal muscle glycogen and subsequent regulation of exercise capacity. Skeletal muscle-specific IRF4 knockout mice show normal body weight and insulin sensitivity, but better exercise capacity and increased glycogen content with unaltered triglyceride levels compared to control mice on chow diet. In contrast, mice overexpression of IRF4 displays decreased exercise capacity and lower glycogen content. Mechanistically, IRF4 regulates glycogen-associated regulatory subunit protein targeting to glycogen (PTG) to manipulate glucose metabolism in skeletal muscle. Knockdown of PTG can reverse the effects imposed by the absence of IRF4 in vivo. These studies reveal a regulatory pathway including IRF4/PTG/glycogen synthesis on controlling exercise capacity.

SUBMITTER: Zhu X

PROVIDER: S-EPMC7539189 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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IRF4 in Skeletal Muscle Regulates Exercise Capacity via PTG/Glycogen Pathway.

Zhu Xiaopeng X Yao Ting T Wang Ru R Guo Shanshan S Wang Xin X Zhou Zhenqi Z Zhang Yan Y Zhuo Xiaozhen X Wang Ruitao R Li John Zhong JZ Liu Tiemin T Kong Xingxing X

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20200801 19

Exercise-induced fatigue and exhaustion are interesting areas for many researchers. Muscle glycogen is critical for physical performance. However, how glycogen metabolism is manipulated during exercise is not very clear. The aim here is to assess the impact of interferon regulatory factor 4 (IRF4) on skeletal muscle glycogen and subsequent regulation of exercise capacity. Skeletal muscle-specific IRF4 knockout mice show normal body weight and insulin sensitivity, but better exercise capacity and ...[more]

PMID: 33042761

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Project description:Background: Exercise mimetics is a proposed class of therapeutics that specifically mimics or enhances the therapeutic effects of exercise. Muscle glycogen and lactate extrusion are critical for physical performance. The mechanism by which glycogen and lactate metabolism are manipulated during exercise remains unclear. This study aimed to assess the effect of miR-92b on the upregulation of exercise training-induced physical performance. Methods: Adeno-associated virus (AAV)-mediated skeletal muscle miR-92b overexpression in C57BLKS/J mice, and global knockout of miR-92b mice were used to explore the function of miR-92b in glycogen and lactate metabolism in skeletal muscle. AAV-mediated UGP2 or MCT4 knockdown in WT or miR-92 knockout mice was used to confirm whether miR-92b regulates glycogen and lactate metabolism in skeletal muscle through UGP2 and MCT4. Body weight, muscle weight, grip strength, running time and distance to exhaustion, and muscle histology were assessed. The expression levels of muscle mass-related and functionrelated proteins were analysed by immunoblotting or immunostaining. Results: Global knockout of miR-92b resulted in normal body weight and insulin sensitivity, but higher glycogen content before exercise exhaustion (0.8538 ± 0.0417 vs 1.043 ± 0.040, **P=0.0087), lower lactate levels after exercise exhaustion (4.133 ± 0.2589 vs 3.207 ± 0.2511, *P=0.0279), and better exercise capacity (running distance to exhaustion, 3616 ± 86.71 vs 4231 ± 90.29, ***P=0.0006; running time to exhaustion, 186.8 ± 8.027 vs 220.8 ± 3.156, **P=0.0028), as compared to those observed in the control mice. Mice skeletal muscle overexpressing miR-92b (both miR-92b-3p and miR-92b-5p) displayed lower glycogen content before exercise exhaustion (0.6318 ± 0.0231 vs 0.535 ± 0.0194, **P=0.0094), and higher lactate accumulation after exercise exhaustion (4.5 ± 0.2394 vs 5.467 ± 0.1892, *P=0.01), and poorer exercise capacity (running distance to exhaustion, 4005 ± 81.65 vs 3228 ± 149.8, ***P＜0.0001; running time to exhaustion, 225.5 ± 7.689 vs 163 ± 6.476, **P=0.001). Mechanistic analysis revealed that miR-92b-3p targets UDP-glucose pyrophosphorylase 2 (UGP2) expression to inhibit glycogen synthesis, while miR-92b-5p represses lactate extrusion by directly target monocarboxylate transporter 4 (MCT4). Knockdown of UGP2 and MCT4 reversed the effects observed in the absence of miR-92b in vivo. Conclusions: This study revealed regulatory pathways, including miR-92b-3p/UGP2/glycogen synthesis and miR-92b-5p/MCT4/lactate extrusion, which could be targeted to control exercise capacity.

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IRF4 in Skeletal Muscle Regulates Exercise Capacity via PTG/Glycogen Pathway.

Publications

IRF4 in Skeletal Muscle Regulates Exercise Capacity via PTG/Glycogen Pathway.

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