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2578-P: Retatrutide Enhances Weight Loss in Female Mice and Preserves Muscle Mass, Strength, and Mitochondrial Efficiency
Abstract   Peer reviewed

2578-P: Retatrutide Enhances Weight Loss in Female Mice and Preserves Muscle Mass, Strength, and Mitochondrial Efficiency

Kyle Baum, Brian O'Neill, Christie Penniman and Gourav Bhardwaj
Diabetes (New York, N.Y.), Vol.75(Suppl 1), p.2578-P
06/01/2026
DOI: 10.2337/db26-2578-P

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Abstract

Introduction and Objective: Recent clinical data shows significant lean mass loss with semaglutide (SEMA) or tirzepatide-induced weight loss. However, the effects of GLP-1, GIP, and/or glucagon receptor agonists on muscle size and function, and sex-based differences are unknown. We determined the effects of Retatrutide (GLP-1, GIP, Glucagon triagonist) on muscle mass, strength, and mitochondrial function in obese male and female mice. Methods: C57Blk6 mice were fed 3 months of 60% fat diet to induce obesity, then were treated with daily injections of Vehicle (VEH) or 10 nmol Retatrutide (RET) for 14 days, or were pair-fed to RET. SEMA 10 nmol was added as a control. Muscle torque at the tibialis anterior (TA) were measured in vivo using Aurora. Muscle tissue was collected for size and permeabilized soleus fibers used for mitochondrial bioenergetics. ANOVA was used for statistics. Results: RET-treated MALE mice loss 27.1% (p<0.01 vs. VEH) body weight, which was not statistically different from pair-fed MALES (20.4%, p<0.01 vs. VEH), or SEMA MALES (19.9%, p<0.01 vs VEH). By contrast, RET FEMALE mice loss 29.8% body weight (p<0.01 vs. VEH), compared to 17.0% in pair-fed (p<0.01 vs. VEH, p<0.01 vs. RET), and 14.2% in SEMA FEMALES (p<0.01 vs VEH, p<0.01 vs RET). Maximal torque at TA was not changed between groups in FEMALE mice. TA mass per tibia length was smaller in RET MALES (1.92 mg/mm vs. 2.34 in VEH, p<0.05) and pair-fed MALES (1.96 mg/mm, p<0.05 vs. VEH), but not FEMALES. Similar decreases were seen in EDL and gastrocnemius mass in MALES, but not FEMALES. We saw no change in SEMA muscle mass compared to VEH. Mitochondrial oxygen consumption tended to decrease in RET groups, but ATP production remained normal, so ATP/O ratio trended higher in RET compared to VEH soleus muscle. Conclusion: Retatrutide enhanced weight loss in FEMALE compared to pair-fed or SEMA. Muscle size decreased in retatrutide and pair-fed MALES. Muscle mass was preserved in retatrutide FEMALES, despite enhanced weight loss vs. pair-fed, and without changes in strength or ATP production.
 Bioenergetics Obesity Body weight loss Females Glucagon Males Mitochondria Oxygen consumption Skeletal muscle Soleus muscle Tibia

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