PMID- 37622333 OWN - NLM STAT- MEDLINE DCOM- 20230912 LR - 20230927 IS - 1470-8736 (Electronic) IS - 0143-5221 (Linking) VI - 137 IP - 17 DP - 2023 Sep 13 TI - Exercise ameliorates skeletal muscle insulin resistance by modulating GRK4-mediated D1R expression. PG - 1391-1407 LID - 10.1042/CS20230664 [doi] AB - Exercise has been recommended as a nonpharmaceutical therapy to treat insulin resistance (IR). Previous studies showed that dopamine D1-like receptor agonists, such as fenoldopam, could improve peripheral insulin sensitivity, while antipsychotics, which are dopamine receptor antagonists, increased susceptibility to Type 2 diabetes mellitus (T2DM). Meanwhile, exercise has been proved to stimulate dopamine receptors. However, whether the dopamine D1 receptor (D1R) is involved in exercise-mediated amelioration of IR remains unclear. We found that the D1-like receptor antagonist, SCH23390, reduced the effect of exercise on lowering blood glucose and insulin in insulin-resistant mice and inhibited the contraction-induced glucose uptake in C2C12 myotubes. Similarly, the opposite was true for the D1-like receptor agonist, fenoldopam. Furthermore, the expression of D1R was decreased in skeletal muscles from streptozotocin (STZ)- and high-fat intake-induced T2DM mice, accompanied by increased D1R phosphorylation, which was reversed by exercise. A screening study showed that G protein-coupled receptor kinase 4 (GRK4) may be the candidate kinase for the regulation of D1R function, because, in addition to the increased GRK4 expression in skeletal muscles of T2DM mice, GRK4 transgenic T2DM mice exhibited lower insulin sensitivity, accompanied by higher D1R phosphorylation than control mice, whereas the AAV9-shGRK4 mice were much more sensitive to insulin than AAV9-null mice. Mechanistically, the up-regulation of GRK4 expression caused by increased reactive oxygen species (ROS) in IR was ascribed to the enhanced expression of c-Myc, a transcriptional factor of GRK4. Taken together, the present study shows that exercise, via regulation of ROS/c-Myc/GRK4 pathway, ameliorates D1R dysfunction and improves insulin sensitivity. CI - (c) 2023 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society. FAU - Tao, Yu AU - Tao Y AUID- ORCID: 0009-0009-2110-8815 AD - Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China. AD - Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China. AD - State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China. FAU - Luo, Wenbin AU - Luo W AD - Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China. AD - Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China. AD - State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China. FAU - Chen, Yue AU - Chen Y AD - Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China. AD - Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China. AD - State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China. FAU - Chen, Caiyu AU - Chen C AD - Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China. AD - Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China. AD - State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China. FAU - Chen, Shengnan AU - Chen S AD - Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China. AD - Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China. AD - State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China. FAU - Li, Xiaoping AU - Li X AUID- ORCID: 0000-0002-5057-0226 AD - Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China. AD - Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China. AD - State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China. FAU - Chen, Ken AU - Chen K AUID- ORCID: 0000-0002-8958-1088 AD - Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China. AD - Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China. AD - State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China. FAU - Zeng, Chunyu AU - Zeng C AUID- ORCID: 0000-0002-5534-0518 AD - Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China. AD - Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China. AD - State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China. AD - Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, P.R. China. AD - Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, P.R. China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - Clin Sci (Lond) JT - Clinical science (London, England : 1979) JID - 7905731 RN - INU8H2KAWG (Fenoldopam) RN - 0 (Insulin) RN - 0 (Reactive Oxygen Species) RN - 0 (Receptors, Dopamine D1) RN - EC 2.7.11.16 (GRK4 protein, mouse) SB - IM MH - Animals MH - Mice MH - *Diabetes Mellitus, Type 2 MH - Fenoldopam MH - Insulin MH - *Insulin Resistance MH - Muscle, Skeletal MH - Reactive Oxygen Species MH - Receptors, Dopamine D1/genetics OTO - NOTNLM OT - G protein-coupled receptor kinase 4 OT - dopamine D1 receptor OT - exercise OT - insulin resistance OT - skeletal muscle EDAT- 2023/08/25 06:42 MHDA- 2023/09/08 06:42 CRDT- 2023/08/25 05:26 PHST- 2023/06/27 00:00 [received] PHST- 2023/08/24 00:00 [revised] PHST- 2023/08/24 00:00 [accepted] PHST- 2023/09/08 06:42 [medline] PHST- 2023/08/25 06:42 [pubmed] PHST- 2023/08/25 05:26 [entrez] AID - 233417 [pii] AID - 10.1042/CS20230664 [doi] PST - ppublish SO - Clin Sci (Lond). 2023 Sep 13;137(17):1391-1407. doi: 10.1042/CS20230664.