Klotho protein deficiency leads to overactivation of mu-calpain.

The klotho mouse is an animal model that prematurely shows phenotypes resembling human aging. Here we report that in homozygotes for the klotho mutation (kl(-/-)), alpha(II)-spectrin is highly cleaved, even before the occurrence of aging symptoms such as calcification and arteriosclerosis. Because alpha(II)-spectrin is susceptible to proteolysis by calpain, we examined the activation of calpain in kl(-/-) mice. m-Calpain was not activated, but mu-calpain was activated at an abnormally high level, and an endogenous inhibitor of calpain, calpastatin, was significantly decreased. Proteolysis of alpha(II)-spectrin increased with decreasing level of Klotho protein. Similar phenomena were observed in normal aged mice. Our results indicate that the abnormal activation of calpain due to the decrease of Klotho protein leads to degradation of cytoskeletal elements such as alpha(II)-spectrin. Such deterioration may trigger renal abnormalities in kl(-/-) mice and aged mice, but Klotho protein may suppress these processes.