Age-related declines in α-Klotho drive progenitor cell mitochondrial dysfunction and impaired muscle regeneration

A. Sahu, H. Mamiya, S. N. Shinde, A. Cheikhi, L. L. Winter, N. V. Vo, D. Stolz, V. Roginskaya, W. Y. Tang, C. St. Croix, L. H. Sanders, M. Franti, B. Van Houten, T. A. Rando, A. Barchowsky & F. Ambrosio

https://www.nature.com/articles/s41467-018-07253-3

• Aged muscle shows a decreased capacity to repair itself after acute injury.   Muscle stem cells (MuSCs) mediate muscle repair, which become activated when muscles are injured. MuSCs show increased apoptosis, decreased proliferation, impairment of mitophagy, senescence, and decreased resistance to stress, with age.
• The gene Klotho encodes a membrane-bound, circulating, hormonal protein in mice and humans; its deficiency is associated with ageing phenotypes including: decreased activity, gait disturbance, cognitive impairment, sarcopenia, and impaired wound repair. Declines in α-Klotho in tissues such as the skin, small intestine, and kidney, have been associated with senescence and stem cell dysfunction.
• In young skeletal muscle, the authors show that the α-Klotho promoter is transiently demethylated under acute muscle injury, which is associated with increased expression. In aged tissue, α-Klotho shows no significant change in methylation in response to muscle injury, and no significant expression. 
• Knockdown of α-Klotho in young animals results in an aged phenotype, with aberrant mitochondrial ultrastructure, decreased mitochondrial bioenergetics, mtDNA damage (perhaps mediated through cardiolipin peroxidation), and senescence.
• Sytematic delivery of exogenous α-Klotho to aged mice rejuvenates muscle progenitor stem cell (MPC) bioenergetics, enhances myofiber regeneration, and muscle function after acute injury.   

Thoughts
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In Figure 6a, the authors show that when aged  MPC are isolated from old mice, and cultured with α-Klotho for 48h, the authors observe a decreased number of mtDNA lesions relative to cells which are not treated with α-Klotho (a difference of about 1 mutation per molecule of mtDNA). This is a pretty huge number of mutations over 48 hrs! It would be fascinating to infer the mtDNA mutation rate from these data.