Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, 15213, PA, USA.
Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, 15261, PA, USA.
Nat Commun. 2018 Nov 19;9(1):4859. doi: 10.1038/s41467-018-07253-3.
While young muscle is capable of restoring the original architecture of damaged myofibers, aged muscle displays a markedly reduced regeneration. We show that expression of the "anti-aging" protein, α-Klotho, is up-regulated within young injured muscle as a result of transient Klotho promoter demethylation. However, epigenetic control of the Klotho promoter is lost with aging. Genetic inhibition of α-Klotho in vivo disrupted muscle progenitor cell (MPC) lineage progression and impaired myofiber regeneration, revealing a critical role for α-Klotho in the regenerative cascade. Genetic silencing of Klotho in young MPCs drove mitochondrial DNA (mtDNA) damage and decreased cellular bioenergetics. Conversely, supplementation with α-Klotho restored mtDNA integrity and bioenergetics of aged MPCs to youthful levels in vitro and enhanced functional regeneration of aged muscle in vivo in a temporally-dependent manner. These studies identify a role for α-Klotho in the regulation of MPC mitochondrial function and implicate α-Klotho declines as a driver of impaired muscle regeneration with age.
虽然年轻的肌肉能够恢复受损肌纤维的原始结构，但衰老的肌肉显示出明显降低的再生能力。我们表明，“抗衰老”蛋白α-Klotho 的表达在年轻受损肌肉中上调，这是由于 Klotho 启动子去甲基化的短暂性。然而，随着年龄的增长，Klotho 启动子的表观遗传控制丢失。体内抑制 α-Klotho 的基因抑制了肌肉祖细胞 (MPC) 谱系的进展并损害了肌纤维的再生，这表明 α-Klotho 在再生级联中起着关键作用。在年轻的 MPC 中沉默 Klotho 会导致线粒体 DNA (mtDNA) 损伤和细胞生物能量的降低。相反，α-Klotho 的补充恢复了体外衰老 MPC 的 mtDNA 完整性和生物能量，以年轻水平，并以时间依赖性方式增强了体内衰老肌肉的功能再生。这些研究确定了 α-Klotho 在调节 MPC 线粒体功能中的作用，并暗示 α-Klotho 的下降是衰老导致肌肉再生受损的驱动因素。
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