MicroRNA-92b in the skeletal muscle regulates exercise capacity via modulation of glucose metabolism

Yang, Shu1,2,3; Yang, Guangyan1,3; Wang, Xinyu1,3; Li, Lixing1,3; Li, Yanchun1,3; Xiang, Jiaqing1,3; Kang, Lin1,3,4; Liang, Zhen1,3

2023-11-01

10.1002/jcsm.13377

JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE   影响因子和分区

2190-5991

2190-6009

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 function-related 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 with 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.

Exercise capacity Glycogen synthesis Lactate extrusion miR-92b Skeletal muscle

SCI

英语

通讯

This work was supported by grants from the National Natural Science Foundation of China (82370876 to Shu Yang, 82170842 and 82371572 to Zhen Liang, 82171556 to Lin Kang), Shenzhen Sustainable Development Science and Technology Special Project, China (No. K["82370876","82170842","82371572","82171556"] ; National Natural Science Foundation of China[KCXFZ20201221173600001] ; Shenzhen Sustainable Development Science and Technology Special Project, China[JCYJ20220818102605013]

Geriatrics & Gerontology ; General & Internal Medicine

Geriatrics & Gerontology ; Medicine, General & Internal

WOS:001107467600001

WILEY

2-s2.0-85177033505

Web of Science

1.Jinan Univ, Clin Med Coll 2, Dept Geriatr, Shenzhen Peoples Hosp, Guangzhou, Peoples R China
2.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen Peoples Hosp, Shenzhen, Peoples R China
3.Shenzhen Peoples Hosp, Guangdong Prov Clin Res Ctr Geriatr, Shenzhen Clin Res Ctr Geriatr, Shenzhen, Peoples R China
4.Shenzhen Peoples Hosp, Biobank Natl Innovat Ctr Adv Med Devices, Shenzhen, Peoples R China

Yang, Shu,Yang, Guangyan,Wang, Xinyu,et al. MicroRNA-92b in the skeletal muscle regulates exercise capacity via modulation of glucose metabolism[J]. JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE,2023,14(6):2925-2938.

Yang, Shu.,Yang, Guangyan.,Wang, Xinyu.,Li, Lixing.,Li, Yanchun.,...&Liang, Zhen.(2023).MicroRNA-92b in the skeletal muscle regulates exercise capacity via modulation of glucose metabolism.JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE,14(6),2925-2938.

Yang, Shu,et al."MicroRNA-92b in the skeletal muscle regulates exercise capacity via modulation of glucose metabolism".JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE 14.6(2023):2925-2938.