Introduction and Objective: There is increasing concern with the amount muscle loss across GLP-1 receptor agonist (GLP1-RA) weight loss drugs (STEP1, SUSTAIN8, SURMOUNT-1, AWARD-11 trials etc). As low muscle mass predicts poor health outcomes and mitochondrial dysfunction is a critical obesogenic and atrophic driver, we developed novel mitochondria-targeted small molecules as muscle-preserving weight loss strategies to correct these musculo-metabolic defects. We identified Myo4 from extensive in vitro and in vivo functional and toxicological screening, including selective muscle accumulation in vivo.Methods: Male C57BL/6JRj mice were fed a high fat diet (60% kcal;D12492) from 5 weeks for 26 weeks then dosed (s.c.,q.d.,T.I.W.) with Myo4 (0.22-2.2mg/kg), semaglutide (10nmol/kg), or both drugs for 4 weeks (n=8-12/group). Body weight, food intake, fasting glucose, insulin, OGTT, eWAT, BAT, muscle weight, and fat:lean redistribution (MRI) were assessed with appropriate statistical analysis.Results: Unlike semaglutide, Myo4 did not decrease initial food intake (0-11 days). Both drugs reduced weight and fat mass, but only Myo4 increased lean mass. Myo4 enhanced the metabolic benefit of semaglutide, boosting lean mass and normalising glucose (Fig.1).Conclusion: Myo4 is a muscle preserving anti-obesogenic and mono-therapeutic for obesity-related indications that could be used in combination with GLP1-RA to prevent muscle mass and/or function loss.
J. Holder: None. R. Torregrossa: None. L. Humbert: None. R. Cousins: None. N. Law: None. J. Rees: None. M. Whiteman: None.
MitoRx Therapeutics Limited, Harwell Oxford, Didcot, Oxfordshire, United Kingdom OX11 0QG
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