Abstract
BackgroundKlotho is a well-known anti-aging hormone, which serves as a suppressor of aging through a variety of mechanisms. Aging of skeletal muscle is concomitant with a decrease in muscle stem cell function resulting in impaired regeneration.MethodsHere we investigate the functional role of the anti-aging hormone Klotho for muscle stem cell function after cardiotoxin-induced injury of skeletal muscle using a klotho hypomorphic mouse line, which is characterized by a premature aging phenotype. Furthermore, we perform floating single myofiber cultures with their adjacent muscle stem cells to investigate the interplay between canonical Wnt signaling and Klotho function.ResultsWe demonstrate that muscle stem cell numbers are significantly decreased in klotho hypomorphic mice. Furthermore, we show that muscle stem cell function is also severely impaired upon loss of klotho expression, in culture and during regeneration in vivo. Moreover, we demonstrate that addition of recombinant Klotho protein inhibits aberrant excessive Wnt signaling in aged muscle stem cells thereby restoring their functionality.ConclusionsThe anti-aging hormone Klotho counteracts aberrant canonical Wnt signaling in muscle stem cells and might be one of the naturally occurring inhibitors of canonical Wnt signaling in skeletal muscle.
Highlights
Klotho is a well-known anti-aging hormone, which serves as a suppressor of aging through a variety of mechanisms
Muscle stem cell numbers are reduced in ΔKlotho mice Several reports suggested that stem cell function in different organs is perturbed in ΔKlotho mice, e.g., adipogenic stem cells [29]
We found a reduction in the number of muscle stem cells in ΔKlotho mice at p56 and p14 while numbers were comparable at p21, a time point when skeletal muscle matures (Fig. 1a–d)
Summary
Klotho is a well-known anti-aging hormone, which serves as a suppressor of aging through a variety of mechanisms. Aging of skeletal muscle is concomitant with a decrease in muscle stem cell function resulting in impaired regeneration. Named satellite cells, are a prerequisite for functional regeneration [2, 3]. Under resting conditions they are quiescent and located under the basal lamina [4]. Muscle stem cell functionality can be affected by intrinsic changes in the cells themselves and changes in the environment—extrinsic changes [1, 4].
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