支持我们对衰老的理解的原则之一是,DNA损伤会引起应激反应,将细胞资源从生长转向维持。一个对比鲜明且看似不可调和的观点是,例如,骨骼肌赋予全身益处。
为了研究这些公理的稳健性,我们通过使用抑制肌肉生长抑制素/激活素信号传导的激活素受体IIB配体陷阱在鼠孕激素模型中诱导肌肉生长。然后研究了生殖小鼠的神经和肌肉功能以及肌肉的细胞概况,肾,肝脏,还有骨头.
我们显示Ercc1Δ/-孕激素小鼠的肌肉经历严重的消瘦(与正常质量相比,后肢肌肉质量减少40-60%),通过使用可溶性IIB型激活素受体(sActRIIB)减弱肌肉生长抑制素/激活素信号传导在很大程度上得到保护(与未处理的progeric相比增加30-62%)。sActRIIB治疗的孕激素小鼠保持肌肉活动(每小时的距离旅行:未经治疗的小鼠与13.7mintreated)andincreasedspecificforce(19.3mN/mgintreatedvs.处理后的24.0mN/mg)。sActRIIb治疗孕激素小鼠还改善了卫星细胞功能,尤其是它们在其天然底物上增殖的能力(未经治疗的孕激素中每纤维2.5个细胞与在培养72小时后,sActRIIB处理的孕激素为5.4)。除了对肌肉的直接保护作用,我们显示了其他器官的全身性改善,包括肾脏的结构和功能;尿液中的蛋白质含量显着降低(白蛋白/肌酐为4.9sActRIIB治疗与15.7未处理),这可能是足细胞足过程正常化的结果,其构成过滤装置(肾小球基底膜厚度在sActRIIB处理后从224降低至177nm)。用活化素配体捕获剂治疗孕鼠可防止肝脏异常的发展,包括多倍体(未经治疗的18.3%vs.8.1%治疗)和骨质疏松症(骨小梁体积;治疗的孕激素小鼠与0.30mm30.14mm3的未经治疗的小鼠,皮质骨体积;0.30mm3在治疗的早孕小鼠与0.22mm3的未处理小鼠)。神经系统异常的发作延迟(约5周),其严重程度降低,在不影响寿命的情况下维持整体健康。
这项研究质疑衰老过程中组织生长和维持组织功能是不相容机制的观点。它强调了未来研究的必要性,以评估基于肌肉生长抑制素/激活素阻断疗法的潜力,以压缩发病率和促进健康衰老。
One of the principles underpinning our understanding of ageing is that DNA damage induces a stress response that shifts cellular resources from growth towards maintenance. A contrasting and seemingly irreconcilable view is that prompting growth of, for example, skeletal muscle confers systemic benefit.
To investigate the robustness of these axioms, we induced muscle growth in a murine
progeroid model through the use of activin receptor IIB ligand trap that dampens myostatin/activin signalling. Progeric mice were then investigated for neurological and muscle function as well as cellular profiling of the muscle, kidney, liver, and bone.
We show that muscle of Ercc1Δ/-
progeroid mice undergoes severe wasting (decreases in hind limb muscle mass of 40-60% compared with normal mass), which is largely protected by attenuating myostatin/activin signalling using soluble activin receptor type IIB (sActRIIB) (increase of 30-62% compared with untreated progeric). sActRIIB-treated
progeroid mice maintained muscle activity (distance travel per hour: 5.6 m in untreated mice vs. 13.7 m in treated) and increased specific force (19.3 mN/mg in untreated vs. 24.0 mN/mg in treated). sActRIIb treatment of
progeroid mice also improved satellite cell function especially their ability to proliferate on their native substrate (2.5 cells per fibre in untreated progeroids vs. 5.4 in sActRIIB-treated progeroids after 72 h in culture). Besides direct protective effects on muscle, we show systemic improvements to other organs including the structure and function of the kidneys; there was a major decrease in the protein content in urine (albumin/creatinine of 4.9 sActRIIB treated vs. 15.7 in untreated), which is likely to be a result in the normalization of podocyte foot processes, which constitute the filtration apparatus (glomerular basement membrane thickness reduced from 224 to 177 nm following sActRIIB treatment). Treatment of the progeric mice with the activin ligand trap protected against the development of liver abnormalities including polyploidy (18.3% untreated vs. 8.1% treated) and osteoporosis (trabecular bone volume; 0.30 mm3 in treated progeroid mice vs. 0.14 mm3 in untreated mice, cortical bone volume; 0.30 mm3 in treated
progeroid mice vs. 0.22 mm3 in untreated mice). The onset of neurological abnormalities was delayed (by ~5 weeks) and their severity reduced, overall sustaining health without affecting lifespan.
This study questions the notion that tissue growth and maintaining tissue function during ageing are incompatible mechanisms. It highlights the need for future investigations to assess the potential of therapies based on myostatin/activin blockade to compress morbidity and promote healthy ageing.