Chronic UCN2 Administration Alters Muscle Mass, Exercise Metabolism, and Exercise Capacity in Lean Mice

Abstract

Urocortin 2 (UCN2) is a member of the corticotropin-releasing hormone (CRH) family and an agonist of the G protein-coupled receptor CRH receptor type 2 (CRHR2), which is highly expressed in skeletal muscle but absent from liver in both rodents and humans. UCN2 overexpression or chronic administration increases muscle mass in both lean and diet-induced obese (DIO) mice and is also believed to increase peripheral insulin sensitivity, reminiscent of the effect of acute exercise. However, how these effects of UCN2 may impact muscle function and exercise capacity remain incompletely understood. We hypothesized that treatment with a long term UCN2 treatment would increase lean and muscle mass and improve aerobic exercise capacity in lean, healthy mice. Lean 10-week-old male C57Bl/6J mice completed treadmill acclimatization and an incremental running test to exhaustion to determine maximal running distance and peak oxygen consumption (VO2). Mice were assigned to sedentary or maximal running groups and were treated with UCN2 for 18 days. After the final dose, body composition was assessed by qNMR. Vehicle- and UCN2-treated mice assigned to the maximal running group completed a second maximal test, and immediately upon completion of exercise, blood glucose was measured, and tissues were collected. Blood glucose and tissues were collected from sedentary vehicle- and UCN2-treated mice in the fed state. UCN2 treatment increased food intake, qNMR lean mass, and individual muscle weights. UCN2-treated mice had reduced maximal running distance, peak VO2, and blood glucose in response to exercise compared to vehicle mice. In addition, UCN2-treated mice had reduced hepatic glycogen in both the sedentary and post maximal exercise states. Gastrocnemius muscle from sedentary UCN2-treated mice had increased glycogen content and reduced phosphorylation of glycogen synthase. Following maximal exercise, UCN2-treated mice had higher gastrocnemius glycogen compared to vehicle mice. This indicated similar total glycogen utilization between treatment groups in response to maximal exercise, despite UCN2-treated mice performing less work. Follow-up studies in sedentary mice demonstrated UCN2 dosing increased phosphorylation of proteins involved in insulin-dependent and -independent glucose uptake in gastrocnemius muscle. These findings indicate that UCN2 affects whole-body and muscle substrate utilization and glucose regulation and signaling which results in increased muscle mass and altered exercise capacity. However, the unpredictability of the effects of UCN2 agonism on these parameters requires much further study. This research was funded by Eli Lilly and Company. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.