Abstract 556: Obese Diabetic Mice Exhibited Severe Intramuscular Lipid Accumulation after Muscle Injury

Abstract

Background: Sarcopenic obesity, a loss of muscle and a concomitant increase in ectopic fat, is reported to increase in life-style related diseases. Especially the prevalence of sarcopenia is greater in patients with type 2 diabetes mellitus (T2DM) than in non-diabetic subjects. Increase in fat filtration enhances insulin resistance and is associated with metabolic risk factors. However, the detailed mechanism of such ectopic fat filtration in muscle of T2DM patients has not been well investigated. Here, we assessed muscle regeneration using muscle-injured models in obese diabetic mice. Methods: Male eight-week-old wild-type mice (C57BL6) and T2DM mice (KKAy) were undergone intramuscular injection of cardiotoxin (Ctx) (100uL/10uM) into tibia. After two weeks, muscle were removed and stained with hematoxylin and eosin. KKAy replaced by bone marrow prepared from GFP-transgenic mice were generated by 8 Gy whole body X-ray irradiation. Cell-differentiation was evaluated by immunofluorescent analysis. Some mice were treated with all trans-retinoic acid (ATRA) and PPAR-gamma antagonist, GW9662. Results: In 26 week-old KKAy, magnetic resonance imaging analysis showed that intramuscular fat deposition was estimated as higher intensity compared with C57BL6 mice. Treatment with Ctx showed a significant increase in honey comb structure which was perilipin positive. KKAy mice exhibited impaired muscle regeneration. Tibial muscle weight was approximately a half in Ctx-injured KKAy. Such change was also observed in another diabetic mouse model, db/db, but not in streptozocin-induced diabetic mice. Fat formation was remarkably increased in aged KKAy compared with younger mice. Several fat formation was GFP-positive in GFP-chimeric mice indicating that fat tissue was partially generated from marrow cells. Fat formation was desmin-negative and vimentin-positive indicating that these are mesenchymal origin. Treatment with ATRA reduced fat filtration. On the other hand, treatment with GW9662 enhanced fat filtration. Conclusion: Obese diabetic mice showed significantly impaired muscle regeneration with replacement of fat deposition, suggesting that diabetes enhanced sarcopenic obesity possibly due to inhibitory effect of cell differentiation.