Georgia Regents University, Augusta, GA 30912, USA.
Exp Gerontol. 2013 Sep;48(9):898-904. doi: 10.1016/j.exger.2013.06.004. Epub 2013 Jul 4.
Loss of muscle and bone mass with age are significant contributors to falls and fractures among the elderly. Myostatin deficiency is associated with increased muscle mass in mice, dogs, cows, sheep and humans, and mice lacking myostatin have been observed to show increased bone density in the limb, spine, and jaw. Transgenic overexpression of myostatin propeptide, which binds to and inhibits the active myostatin ligand, also increases muscle mass and bone density in mice. We therefore sought to test the hypothesis that in vivo inhibition of myostatin using an injectable myostatin propeptide (GDF8 propeptide-Fc) would increase both muscle mass and bone density in aged (24 mo) mice. Male mice were injected weekly (20 mg/kg body weight) with recombinant myostatin propeptide-Fc (PRO) or vehicle (VEH; saline) for four weeks. There was no difference in body weight between the two groups at the end of the treatment period, but PRO treatment significantly increased mass of the tibialis anterior muscle (+ 7%) and increased muscle fiber diameter of the extensor digitorum longus (+ 16%) and soleus (+ 6%) muscles compared to VEH treatment. Bone volume relative to total volume (BV/TV) of the femur calculated by microCT did not differ significantly between PRO- and VEH-treated mice, and ultimate force (Fu), stiffness (S), toughness (U) measured from three-point bending tests also did not differ significantly between groups. Histomorphometric assays also revealed no differences in bone formation or resorption in response to PRO treatment. These data suggest that while developmental perturbation of myostatin signaling through either gene knockout or transgenic inhibition may alter both muscle and bone mass in mice, pharmacological inhibition of myostatin in aged mice has a more pronounced effect on skeletal muscle than on bone.
随着年龄的增长，肌肉和骨量的流失是老年人跌倒和骨折的重要原因。肌肉生长抑制素缺乏与小鼠、狗、牛、羊和人类的肌肉量增加有关，缺乏肌肉生长抑制素的小鼠在四肢、脊柱和颌骨中表现出骨密度增加。肌肉生长抑制素前肽的转基因过表达，该前肽与活性肌肉生长抑制素配体结合并抑制其活性，也会增加小鼠的肌肉量和骨密度。因此，我们试图验证以下假设：在体内使用可注射的肌肉生长抑制素前肽（GDF8 前肽-Fc）抑制肌肉生长抑制素，会增加 24 月龄（老年）小鼠的肌肉量和骨密度。雄性小鼠每周（20mg/kg 体重）接受重组肌肉生长抑制素前肽-Fc（PRO）或载体（VEH；生理盐水）治疗 4 周。在治疗期末，两组小鼠的体重没有差异，但 PRO 治疗显著增加了比目鱼肌（+7%）和伸趾长肌（+16%）和比目鱼肌（+6%）的肌肉纤维直径。通过 microCT 计算的股骨相对于总体积（BV/TV）的骨体积没有显著差异，三点弯曲试验测量的最终力（Fu）、刚度（S）和韧性（U）也没有显著差异。组织形态计量学分析也显示，PRO 治疗对骨形成或骨吸收没有影响。这些数据表明，尽管肌肉生长抑制素信号的发育干扰通过基因敲除或转基因抑制都可能改变小鼠的肌肉和骨量，但在老年小鼠中，肌肉生长抑制素的药理学抑制对骨骼肌的影响比骨骼更为显著。
