Klotho Protein Deficiency Leads to Overactivation of μ-Calpain

Abstract

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 ؊/؊ ), ␣ II -spectrin is highly cleaved, even before the occurrence of aging symptoms such as calcification and arteriosclerosis. Because ␣ II -spectrin is susceptible to proteolysis by calpain, we examined the activation of calpain in kl ؊/؊ mice. m-Calpain was not activated, but -calpain was activated at an abnormally high level, and an endogenous inhibitor of calpain, calpastatin, was significantly decreased. Proteolysis of ␣ 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 ␣ II -spectrin. Such deterioration may trigger renal abnormalities in kl ؊/؊ mice and aged mice, but Klotho protein may suppress these processes.

Klotho is associated with VEGF receptor-2 and the transient receptor potential canonical-1 Ca 2+ channel to maintain endothelial integrity

“…Hyperactivation of calpain causes damage to renal epithelial cells in Klotho-deficient mice (17). We observed that calpain and caspase-3 activities against exogenous substrate in the aorta from Klotho-deficient mice were 130% and 35% higher, respectively, than in WT mice ( Fig.…”

“…2A). Calpain activities were evaluated further by determining the endogenous level of αII-spectrin, a cleaved substrate fragment that is highly sensitive to calpain (17). αII-spectrin is cleaved at particular site by calpain, yielding a 136-kDa fragment (N-terminal cleaved products) and a 148-kDa fragment (C-terminal cleaved products).…”

Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1 , and enhances skeletal muscle force in aging sedentary mice

“…BDA‐410 is a synthetic Leu‐Leu peptidomimetic that significantly attenuates various disease conditions (Carragher, 2006), including memory and synaptic transmission in a mouse model of Alzheimer disease and signs of premature aging in a mouse model of kotho deficiency (Manya et al ., 2002; Trinchese et al ., 2008). BDA‐410 strongly and reversibly inhibits cysteine proteases but not serine or aspartic proteinases.…”

Complete lack of vitamin C intake generates pulmonary emphysema in senescence marker protein-30 knockout mice

“…When disrupted, ␣-Klotho, a regulator of calcium metabolism in the plasma membrane, is associated with a premature aging-like phenotype including emphysema (16,26). Additionally, the lack of ␣-Klotho induces hyperfunction of renal tubular 1␣-hydroxylase resulting in an abnormal increase of serum Ca 2ϩ , which activates the calcium-dependent matrix proteases such as calpain and induces emphysema (29). We anticipate a need to examine the possible role of intracellular calcium homeostasis as well as oxidative stress in the development of aging-like phenotypes in SMP30 KO mice.…”