UCLA

Cellular stress resistance against inflammatory and metabolic insult is critical for disease prevention and longevity. The heat shock response is an evolutionarily conserved defense system engaged during stress to maintain cellular homeostasis. Basal HSP72 levels and induction response to cellular stress are diminished in muscle from obese and type 2 diabetic patients and overexpressed during endurance exercise in healthy lean individuals. Recently, studies in HSP72 knockout mice have shown that HSP72 is a critical regulator of stress-induced mitochondrial triage signaling via Parkin, a ubiquitin ligase that tags mitochondrial membrane proteins for degradation. However, the underlying mechanisms of HSP72 on mitochondrial dynamics remain largely unresolved.

The purpose of this investigation was to determine the effect of restoring muscle HSP72 in male HSP72+/- mice on mitochondrial dynamics including fusion, fission, and mitophagy. Considering previous observations, it is hypothesized that HSP72 overexpression improves mitochondrial health by regulating Parkin and downstream proteins associated with fission and fusion. HSP72+/- mice expressing an inducible HSP72 transgene (HSP72-Tg) or mice with a global null mutation of HSP72 genes (HSP72-KO) were studied and compared phenotypically to aged-matched wildtype (WT) animals. Western blots revealed increased Parkin and decreased pDRP1 S637 protein in HSP72-KO muscle, however these changes in muscle protein and phospho-protein events were prevented by restoration of muscle HSP72 in HSP72-Tg mice. Furthermore, LC3 II/I was increased in muscle from HSP72-Tg mice over WT, suggesting that HSP72 promotes autophagy. Finally, restoration of muscle HSP72 in HSP72-Tg mice improved insulin-stimulated glucose uptake, which was significantly reduced from WT in HSP72-KO mice. Collectively these data support that HSP72 is a viable therapeutic target to combat insulin resistance and metabolic dysfunction associated with type 2 diabetes.