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Objective: To test the hypothesis that restored muscle mass achieved through deletion of myostatin improves angiogenesis in obese mice through the resolution of myosteatosis. Methods: db/db mice, a well-described model of obesity, were crossed with mice lacking myostatin (MSTN KO), a myokine that negatively regulates muscle differentiation and growth, or stearoyl Co-A desaturase 1 (SCD1 KO), the rate limiting enzyme for oleate synthesis and subsequent triglyceride production, to generate db +/-_MSTN +/- and db +/-_SCD1 +/- mice. We utilized confocal and nuclear magnetic resonance (NMR) spectroscopy to assess skeletal muscle (SKM) histology and morphology in db +/-_MSTN +/- and db +/-_SCD1 +/- mice. Muscle lipid content was analyzed via mass spectrometry. Femoral artery ligation was used to stimulate in vivo angiogenesis in response to ischemia; whereas, 1mm aortic rings cultured in ECBM (2% FBS) were used to study ex vivo angiogenesis. Gene expression was assessed by RNA-Seq with protein expression follow-up in isolated gastrocnemius SKM via RT-qPCR and western blotting. Results: As previously described, MSTN deletion results in significantly increased muscle mass without altering whole-body mass or fat percentage in obese db/db mice. Additionally, we observed that obesity inhibits and MSTN deletion restores angiogenesis in both hind limb ischemia and aortic ring assay models. Despite persistent plasma lipedema, ectopic lipid deposition in SKM (Myosteatosis) was largely ameliorated in obese mice lacking MSTN, a reduction largely explained by a decrease in tissue triglyceride levels. Confocal microscopy revealed the accumulation of lipid in obese mouse myocytes that was lacking in obese mice with MSTN KO. RNA-Seq analysis of SKM exposed marked upregulation of lipogenesis pathways, notably the expression of SCD1. SCD1 was elevated at both the protein and RNA levels in db -_MSTN + SKM but not in db -_MSTN - SKM. Similar to MSTN KO, confocal imaging reveals that SCD1 deletion reverses lipid accumulation in obese mice. Conclusion: In summary, restored muscle mass in obese mice provides potent protection to vascular and metabolic health. A potential correlate of this improvement is the resolution of myosteatosis in obese MSTN KO mice. These data suggest that resolution of myosteatosis, independent of muscle mass, may afford similar protection, possibly by targeted deletion or blockade of SCD1. A. C. Guilfoyle-Speese is supported by Kirschstein National Research Service Award (NRSA) Institutional Research Training Grant (T32) T32HL155011. D.W. Stepp and D.J. Fulton are supported by NIH 1R01HL147159. This is the full abstract presented at the American Physiology Summit 2023 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.