Debilitating muscle-disuse atrophy in aging or obesity has huge socioeconomic impact. Since nitric oxide (NO) mediates muscle satellite cell activation and induces hypertrophy with exercise in old mice, we tested whether treatment with the NO donor, isosorbide dinitrate (ISDN), during hind limb suspension would reduce atrophy. Mice were suspended 18 days, with or without daily ISDN (66 mg/kg). Muscles were examined for atrophy (weight, fiber diameter); regulatory changes in atrogin-1 (a negative regulator of muscle mass), myostatin (inhibits myogenesis), and satellite cell proliferation; and metabolic responses in myosin heavy chains (MyHCs), liver lipid, and hypothalamic gene expression. Suspension decreased muscle weight and weight relative to body weight between 25–55%, and gastrocnemius fiber diameter vs. controls. In young-adult mice, ISDN attenuated atrophy by half or more. In quadriceps, ISDN completely prevented the suspension-induced rise in atrogin-1 and drop in myostatin precursor, and attenuated the changes in MyHCs 1 and 2b observed in unloaded muscles without treatment. Fatty liver in suspended young-adult mice was also reduced by ISDN; suspended young mice had higher hypothalamic expression of the orexigenic agouti-related protein, Agrp than controls. Notably, a suspension-induced drop in muscle satellite cell proliferation by 25–58% was completely prevented (young mice) or attenuated (halved, in young-adult mice) by ISDN. NO-donor treatment has potential to attenuate atrophy and metabolic changes, and prevent regulatory changes during disuse and offset/prevent wasting in age-related sarcopenia or space travel. Increases in precursor proliferation resulting from NO treatment would also amplify benefits of physical therapy and exercise.

在衰老或肥胖中使肌肉废用的萎缩性衰弱具有巨大的社会经济影响。由于一氧化氮（NO）介导肌肉卫星细胞的活化并在运动中诱发老年小鼠肥大，因此我们测试了在后肢悬吊过程中用NO供体硝酸异山梨酯（ISDN）进行治疗是否可以减少萎缩。在有或没有每日ISDN（66 mg / kg）的情况下将小鼠悬浮18天。检查肌肉的萎缩（重量，纤维直径）；atrogin-1（肌肉质量的负调节剂），myostatin（抑制肌发生）和卫星细胞增殖的调节变化；和肌球蛋白重链（MyHCs），肝脂质和下丘脑基因表达中的代谢反应。与对照组相比，悬架降低了肌肉重量和相对于体重的重量（25-55％），腓肠肌纤维直径也降低了。在成年小鼠中 ISDN萎缩了一半或更多。在股四头肌中，ISDN完全阻止了悬浮液诱导的atrogin-1的升高和肌生长抑制素前体的下降，并减弱了未经治疗的空腹肌肉中MyHCs 1和2b的变化。ISDN还减少了成年幼鼠的脂肪肝。悬浮的年轻小鼠的下丘脑中的食源性刺豚鼠相关蛋白表达较高，Agrp比控件。值得注意的是，由ISDN完全阻止了悬浮液诱导的肌肉卫星细胞增殖下降25-58％（年轻的小鼠）或减弱了（在成年小鼠中减半）。NO供体治疗具有减少萎缩和代谢变化的潜力，并能防止在与年龄相关的肌肉减少症或太空旅行中的停用和抵消/预防浪费过程中发生监管变化。由NO治疗导致的前体增殖的增加也将扩大物理疗法和运动的益处。