Department of Comparative Biomedical Sciences, Royal Veterinary College, University of London, London, United Kingdom;
Am J Physiol Endocrinol Metab. 2014 Apr 1;306(7):E814-23. doi: 10.1152/ajpendo.00586.2013. Epub 2014 Jan 28.
Insulin resistance (IR) in skeletal muscle is a prerequisite for type 2 diabetes and is often associated with obesity. IR also develops alongside muscle atrophy in older individuals in sarcopenic obesity. The molecular defects that underpin this syndrome are not well characterized, and there is no licensed treatment. Deletion of the transforming growth factor-β family member myostatin, or sequestration of the active peptide by overexpression of the myostatin propeptide/latency-associated peptide (ProMyo) results in both muscle hypertrophy and reduced obesity and IR. We aimed to establish whether local myostatin inhibition would have a paracrine/autocrine effect to enhance glucose disposal beyond that simply generated by increased muscle mass, and the mechanisms involved. We directly injected adeno-associated virus expressing ProMyo in right tibialis cranialis/extensor digitorum longus muscles of rats and saline in left muscles and compared the effects after 17 days. Both test muscles were increased in size (by 7 and 11%) and showed increased radiolabeled 2-deoxyglucose uptake (26 and 47%) and glycogen storage (28 and 41%) per unit mass during an intraperitoneal glucose tolerance test. This was likely mediated through increased membrane protein levels of GLUT1 (19% higher) and GLUT4 (63% higher). Interestingly, phosphorylation of phosphoinositol 3-kinase signaling intermediates and AMP-activated kinase was slightly decreased, possibly because of reduced expression of insulin-like growth factor-I in these muscles. Thus, myostatin inhibition has direct effects to enhance glucose disposal in muscle beyond that expected of hypertrophy alone, and this approach may offer potential for the therapy of IR syndromes.
骨骼肌胰岛素抵抗（IR）是 2 型糖尿病的前提条件，通常与肥胖有关。IR 也会在肥胖的老年人中与肌肉萎缩同时发生。支撑这种综合征的分子缺陷尚未得到很好的描述，也没有许可的治疗方法。肌生成抑制素（myostatin）转化生长因子-β家族成员的缺失，或通过过度表达肌生成抑制素前肽/潜伏相关肽（ProMyo）来隔离活性肽，会导致肌肉肥大和肥胖及 IR 减少。我们旨在确定局部肌生成抑制是否会产生旁分泌/自分泌效应，从而增强葡萄糖的摄取，超出单纯增加肌肉质量所产生的效果，以及涉及的机制。我们直接在大鼠右侧比目鱼肌/趾长伸肌中注射表达 ProMyo 的腺相关病毒，而在左侧注射生理盐水，并在 17 天后比较其效果。两种测试肌肉的大小都增加了（分别增加了 7%和 11%），并且在腹腔内葡萄糖耐量试验中每单位质量的放射性标记 2-脱氧葡萄糖摄取（分别增加了 26%和 47%）和糖原储存（分别增加了 28%和 41%）。这可能是通过增加 GLUT1（高 19%）和 GLUT4（高 63%）的膜蛋白水平来介导的。有趣的是，磷酸肌醇 3-激酶信号转导中间物和 AMP 激活的蛋白激酶的磷酸化略有下降，这可能是由于这些肌肉中胰岛素样生长因子-I 的表达减少。因此，肌生成抑制对肌肉中葡萄糖摄取的增强具有直接作用，超出了单纯肥大所预期的作用，这种方法可能为 IR 综合征的治疗提供了潜力。
