Nunan Emily, Huff Denton R, Gore Jillian L, Wright Carson L, Harris Tag, Butler Landon, Padgett Caleb A, Rochowski Matthew T, Lovern Pamela C, Boolani Ali, Valdez Cammi, Butcher Joshua T
Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA.
Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
Int J Mol Sci. 2025 May 18;26(10):4830. doi: 10.3390/ijms26104830.
Type 1 Diabetes Mellitus (T1D) is a disease characterized by the destruction of pancreatic beta cells. The subsequent loss of insulin production results in hyperglycemia, muscle wasting, and vascular dysfunction. Due to an inability to appropriately maintain glucose homeostasis, patients afflicted with T1D suffer from increased morbidity and early mortality. Skeletal muscle is the body's largest metabolic reservoir, absorbing significant amounts of glucose from the bloodstream and physical exercise is known to improve and prevent the progression of pathological outcomes, but many T1D patients are unable to exercise at a level that conveys benefit. Thus, directly targeting muscle mass and function may prove beneficial for improving T1D patient outcomes, independent of exercise. A potent negative regulator of skeletal muscle has been identified as being upregulated in T1D patients, namely the myokine myostatin. Our hypothesis is that targeting myostatin (via genetic deletion) will prevent glucose dysfunction in a T1D model, preserve skeletal muscle function, and protect against vascular and renal dysfunction. Our methods utilized adult male mice with (WT) and without myostatin (Myo KO), in combination with the chemical induction of T1D (streptozotocin). Experimental outcomes included the assessment of glucose homeostasis (plasma glucose, HbA1c, IGTT), metabolism, muscle function (in vivo plantarflexion), and skeletal muscle vascular function (ex vivo pressure myography). Our results described systemic benefits from myostatin deletion in the T1D model, independent of insulin, including the following: inhibition of T1D-induced increases in plasma glucose, prevention of functional deficits in muscle performance, and preservation of fluid dynamics. Further, endothelial function was preserved with myostatin deletion. Taken together, these data inform upon the use of myostatin inhibition as a therapeutic target for effective treatment and management of the cardiometabolic and skeletal muscle dysfunction that occurs with T1D.
1型糖尿病（T1D）是一种以胰腺β细胞破坏为特征的疾病。随后胰岛素分泌丧失导致高血糖、肌肉萎缩和血管功能障碍。由于无法适当维持葡萄糖稳态，患有T1D的患者发病率增加且过早死亡。骨骼肌是人体最大的代谢储备库，从血液中吸收大量葡萄糖，并且已知体育锻炼可改善和预防病理结果的进展，但许多T1D患者无法进行有益的运动。因此，直接针对肌肉质量和功能可能对改善T1D患者的预后有益，而与运动无关。已确定一种有效的骨骼肌负调节因子在T1D患者中上调，即肌动蛋白抑制素。我们的假设是，靶向肌动蛋白抑制素（通过基因缺失）将预防T1D模型中的葡萄糖功能障碍，保留骨骼肌功能，并预防血管和肾功能障碍。我们的方法使用了有（WT）和没有肌动蛋白抑制素（Myo KO）的成年雄性小鼠，并结合T1D的化学诱导（链脲佐菌素）。实验结果包括评估葡萄糖稳态（血糖、糖化血红蛋白、胰岛素耐量试验）、代谢、肌肉功能（体内足底屈曲）和骨骼肌血管功能（体外压力肌动描记法）。我们的数据表明，在T1D模型中，肌动蛋白抑制素缺失具有全身性益处，与胰岛素无关，包括以下方面：抑制T1D诱导的血糖升高、预防肌肉性能的功能缺陷以及保持流体动力学。此外，肌动蛋白抑制素缺失可保留内皮功能。综上所述，这些数据为将肌动蛋白抑制素抑制作为治疗靶点用于有效治疗和管理T1D伴发的心脏代谢和骨骼肌功能障碍提供了依据。
