Exercise suppresses mouse systemic AApoAII amyloidosis through enhancement of the p38 MAPK signaling pathway

Exercise interventions are beneficial for reducing the risk of age-related diseases, including amyloidosis, but the underlying molecular links remain unelucidated. Here, we investigated the protective role of interval exercise training in a mouse model of age-related systemic apolipoprotein A-II amyloidosis (AApoAII) and elucidated potential mechanisms. Mice subjected to sixteen weeks of exercise improved whole-body physiologic functions and exhibited substantial inhibition of amyloidosis, particularly in the liver and spleen. Exercise activated the hepatic p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway and the downstream transcription factor tumor suppressor p53. This activation resulted in elevated expression and phosphorylation of heat shock protein beta-1 (HSPB1), a chaperone that defends against protein aggregation. In the amyloidosis-induced mice, the hepatic p38 MAPK-related adaptive responses were additively enhanced by exercise. We observed that with exercise, greatly increased amounts of phosphorylated HSPB1 accumulated at amyloid deposition areas, which we suspect to inhibit amyloid fibril formation. Collectively, our findings conclude exercise-activated, specific chaperone prevention of amyloidosis, and suggest that exercise may amplify intracellular stress-related protective adaptation pathways against age-associated disorders such as amyloidosis. Overall design: Investigation liver mRNA profile in response to 16-week interventions of exercise and amyloidosis