Negative Impact of p21-Activated Kinase 4-Mediated AMP-Activated Protein Kinase Inhibition on Sarcopenia in Mice and Humans.

ABSTRACT: We recently identified that AMP-activated protein kinase (AMPK) α2 phosphorylation at S491 is mediated by p21-activated kinase 4 (PAK4), leading to muscular and systemic insulin resistance. This study examined how muscle PAK4 deletion affects atrophy in male mice and its link to human sarcopenia. Dexamethasone treatment increased the mRNA and protein levels of PAK4, which was partially the result of glucocorticoid response elements activation in the promoter of the Pak4 gene. Muscle-specific Pak4 knockout mice were protected from both dexamethasone- and denervation-induced muscle atrophy. Likewise, treatment with a proteolysis-targeting chimera (PROTAC) targeting PAK4 also mitigated muscle atrophy. PAK4 inhibition alleviated mitochondrial dysfunction and enhanced the expressi

SUBMITTER: Du J 

PROVIDER: S-EPMC12664904 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature