Department of Anesthesiology, Medical Faculty Mannheim, University of Heidelberg, 68169 Mannheim, Germany.
Myomedix GmbH, 69151 Neckargemünd, Germany.
Int J Mol Sci. 2021 Feb 23;22(4):2225. doi: 10.3390/ijms22042225.
The muscle-specific ubiquitin ligase MuRF1 regulates muscle catabolism during chronic wasting states, although its roles in general metabolism are less-studied. Here, we metabolically profiled MuRF1-deficient knockout mice. We also included knockout mice for MuRF2 as its closely related gene homolog. MuRF1 and MuRF2-KO (knockout) mice have elevated serum glucose, elevated triglycerides, and reduced glucose tolerance. In addition, MuRF2-KO mice have a reduced tolerance to a fat-rich diet. Western blot and enzymatic studies on MuRF1-KO skeletal muscle showed perturbed FoxO-Akt signaling, elevated Akt-Ser-473 activation, and downregulated oxidative mitochondrial metabolism, indicating potential mechanisms for MuRF1,2-dependent glucose and fat metabolism regulation. Consistent with this, the adenoviral re-expression of MuRF1 in KO mice normalized Akt-Ser-473, serum glucose, and triglycerides. Finally, we tested the MuRF1/2 inhibitors MyoMed-205 and MyoMed-946 in a mouse model for type 2 diabetes mellitus (T2DM). After 28 days of treatment, T2DM mice developed progressive muscle weakness detected by wire hang tests, but this was attenuated by the MyoMed-205 treatment. While MyoMed-205 and MyoMed-946 had no significant effects on serum glucose, they did normalize the lymphocyte-granulocyte counts in diabetic sera as indicators of the immune response. Thus, small molecules directed to MuRF1 may be useful in attenuating skeletal muscle strength loss in T2DM conditions.
肌肉特异性泛素连接酶 MuRF1 调节慢性消耗状态下的肌肉分解代谢，尽管其在一般代谢中的作用研究较少。在这里，我们对 MuRF1 缺失型敲除小鼠进行了代谢特征分析。我们还包括了 MuRF2 缺失型敲除小鼠，因为它是其密切相关的基因同源物。MuRF1 和 MuRF2-KO（敲除）小鼠的血清葡萄糖升高，甘油三酯升高，葡萄糖耐量降低。此外，MuRF2-KO 小鼠对高脂肪饮食的耐受性降低。对 MuRF1-KO 骨骼肌的 Western blot 和酶学研究显示，FoxO-Akt 信号受到干扰，Akt-Ser-473 激活升高，氧化线粒体代谢下调，表明 MuRF1、2 依赖的葡萄糖和脂肪代谢调节的潜在机制。与此一致的是，MuRF1 在 KO 小鼠中的腺病毒再表达使 Akt-Ser-473、血清葡萄糖和甘油三酯正常化。最后，我们在 2 型糖尿病（T2DM）小鼠模型中测试了 MuRF1/2 抑制剂 MyoMed-205 和 MyoMed-946。经过 28 天的治疗，T2DM 小鼠在 wire hang 测试中表现出进行性肌肉无力，但 MyoMed-205 治疗可减轻这种情况。虽然 MyoMed-205 和 MyoMed-946 对血清葡萄糖没有显著影响，但它们确实使糖尿病血清中的淋巴细胞-粒细胞计数正常化，作为免疫反应的指标。因此，针对 MuRF1 的小分子可能有助于减轻 T2DM 条件下的骨骼肌强度损失。
