Department of Physiology, The University of Melbourne, Melbourne, Victoria, Australia.
FASEB J. 2010 Nov;24(11):4433-42. doi: 10.1096/fj.10-159608. Epub 2010 Jul 12.
Sarcopenia is the progressive loss of skeletal muscle mass and function with advancing age, leading to reduced mobility and quality of life. We tested the hypothesis that antibody-directed myostatin inhibition would attenuate the decline in mass and function of muscles of aged mice and that apoptosis would be reduced. Eighteen-month-old C57BL/6 mice were treated for 14 wk with a once-weekly injection of saline (control, n=9) or a mouse chimera of anti-human myostatin antibody (PF-354, 10 mg/kg; n=12). PF-354 prevented the age-related reduction in body mass and increased soleus, gastrocnemius, and quadriceps muscle mass (P<0.05). PF-354 increased fiber cross-sectional area by 12% and enhanced maximum in situ force of tibialis anterior (TA) muscles by 35% (P<0.05). PF-354 increased the proportion of type IIa fibers by 114% (P<0.01) and enhanced activity of oxidative enzymes (SDH) by 39% (P<0.01). PF-354 reduced markers of apoptosis in TA muscle cross-sections by 56% (P<0.03) and reduced caspase3 mRNA by 65% (P<0.04). Antibody-directed myostatin inhibition attenuated the decline in mass and function of muscles of aging mice, in part, by reducing apoptosis. These observations identify novel roles for myostatin in regulation of muscle mass and highlight the therapeutic potential of antibody-directed myostatin inhibition for sarcopenia.
肌肉减少症是随着年龄增长骨骼肌质量和功能逐渐丧失的一种疾病，会导致活动能力下降和生活质量降低。我们假设，抗体定向抑制肌肉生长抑制素（myostatin）可减轻老年小鼠肌肉质量和功能的下降，减少细胞凋亡。我们用每周一次的盐水（对照组，n=9）或抗人肌肉生长抑制素抗体（PF-354，10mg/kg；n=12）的鼠嵌合体对 18 月龄 C57BL/6 小鼠进行了 14 周的治疗。PF-354 可预防与年龄相关的体重减轻，并增加比目鱼肌、腓肠肌和四头肌的质量（P<0.05）。PF-354 增加了 12%的纤维横截面积，并使胫骨前肌（TA）的最大原位力提高了 35%（P<0.05）。PF-354 使 IIa 型纤维的比例增加了 114%（P<0.01），并使氧化酶（SDH）的活性增加了 39%（P<0.01）。PF-354 使 TA 肌横切片中的细胞凋亡标志物减少了 56%（P<0.03），并使 caspase3mRNA 减少了 65%（P<0.04）。抗体定向抑制肌肉生长抑制素可减轻衰老小鼠肌肉质量和功能的下降，部分原因是减少了细胞凋亡。这些观察结果确定了肌肉生长抑制素在调节肌肉质量中的新作用，并突出了抗体定向抑制肌肉生长抑制素治疗肌肉减少症的治疗潜力。
