Abstract 504: Muscle Regeneration is Impaired in Diabetic Mice

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Background Sarcopenia is the degenerative loss of skeletal muscle mass which impaired quality of life in the elderly. On the other hand, sarcopenic obesity which is a loss of muscle and a concomitant increase in 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. However, the detailed mechanism of such muscle degeneration has not been well established. Here, we investigated muscle regeneration using muscle-injured models in life-style related disease mouse model such as angiotensin II overexpression mice for hypertension and obese diabetic mice for diabetes.

Methods Male eight-week-old wild-type mice (C57BL6), Tsukuba hypertensive mice (transgenic mice carrying human renin and angiotensinogen genes) 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.

Results Treatment with Ctx showed increased muscle satellite cells where nucleuses were observed in the center of cells. In Tsukuba hypertensive mice, inflammatory cells were significantly accumulated in muscle compared with C57BL6, but muscle regeneration was not significantly impaired. KKAy mice exhibited impaired muscle regeneration. Tibia weight was a half in Ctx-injected KKAy compared with Ctx non-injected KKAy, and Ctx-injected and non-injected C57BL6 tibia. Moreover, remarkable fat deposition was observed in Ctx-treated muscle of KKAy. Such change was also observed in another diabetic mouse model, db/db, but not in streptozocin-induced diabetic mice. Fat deposition was remarkably increased in aged KKAy (6-month-old) compared with younger mice (8-week-old). In GFP-chimeric mice, fat tissue showed highly GFP-positive indicating that fat tissue was generated from marrow cells.

Conclusion Diabetic mice showed significantly impaired muscle regeneration with fat deposition, suggesting that diabetes enhanced sarcopenic obesity possibly due to inhibitory effect of marrow cell differentiation.

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