Satellite cell proliferation and activation are activated by HIIT exercise and dampened by the klotho transgene through the reduction of canonical Wnt signaling.
The regenerative capacity of skeletal muscle requires muscle stem cells called satellite cells. Muscle injuries activate satellite cells to proliferate and then they either differentiate and fuse to existing muscle fibers, or they return to their quiescent state. The necessity of satellite cell proliferation and fusion for hypertrophic growth caused by increased muscle loading is contested (Egner et al. 2017). Although some studies demonstrate that satellite cells are required for hypertrophic growth after synergist ablation, other investigations show that hypertrophy can occur in muscles that are satellite-cell-deficient (Englund et al. 2011). We analyzed a high intensity interval training (HIIT) protocol that was designed to induce muscle growth (Goh et. al 2019) to determine whether growth in that model was accompanied by expansion of satellite cell numbers. Although satellite cell proliferation and activation were both increased following HIIT, hypertrophy did not occur. This suggests that satellite cell proliferation and activation are not coupled to muscle hypertrophy in HIIT or that the magnitude of expansion of satellite cell numbers was insufficient to increase muscle growth. We then tested whether further expansion of satellite cell numbers in HIIT would produce hypertrophy by subjecting mice that express a transgene encoding Klotho to HIIT because our previous work has shown that Klotho can increase satellite cell proliferation in vitro and their numbers in vivo. Contrary to our expectation, the Klotho transgene attenuated the increases in satellite cell proliferation and activation that occurred in wild-type mice. We then explored the mechanism through which Klotho could attenuate satellite cell proliferation caused by exercise. Because previous investigators showed that signaling through the Wnt-β-catenin pathway increases satellite cell activation in exercised muscle (Fujumaki et al. 2014) and because Klotho can inhibit Wnt signaling in other cell types, we assayed whether expression of the Klotho transgene reduced Wnt-signaling in satellite cells in exercised muscle. Our findings showed that wild-type, exercised mice experienced increased β-catenin signaling in satellite cells after exercise, but the Klotho transgene diminished that effect. These findings suggest that Klotho may attenuate satellite cell activation in exercised muscle by inhibiting the canonical Wnt signaling pathway.