Month‐long AICAR Treatment Reverses Age‐related mTOR Pathway Hyperactivity

Abstract

Sarcopenia is a condition defined by a loss of muscle mass with aging. It is associated with changes in many metabolic pathways. One of these is the mechanistic target of rapamycin (mTOR) pathway, which is chronically activated in aged skeletal muscle under basal conditions. This mTOR hyperactivity is thought to deactivate autophagy, leading to accumulation of defective cell machinery thereby potentially contributing to age‐related muscle dysfunction. AMP‐activated protein kinase (AMPK) acts as an inhibitor of the mTOR pathway. AMPK activation is generally suppressed in sarcopenic muscle, which may contribute to the age‐related increase in mTOR activity. The purpose of this study was to determine if chronic AICAR treatment could reverse mTOR hyperactivation in sarcopenic muscle. To do this, young adult (YA; 5 mo.) and old (O; 23 mo.) C57Bl/6 mice were injected with either AICAR (0.3 – 0.5 mg/g body weight) or saline for one month (31 days). Twenty‐four hours after the final AICAR injection, muscle was harvested and phosphorylation of mTOR‐related signaling components was measured. Sestrin2 protein, which promotes AMPK activity, was decreased in O vs. YA muscles, but was not affected by AICAR. Phosphorylation of both p70S6 kinase (S6k) and ribosomal protein S6 (rpS6) was significantly (p ≤ 0.05) elevated in saline‐treated O vs. YA muscles, similar to previous findings. S6k and rpS6 phosphorylation was unaffected by AICAR in YA muscles, but was decreased by AICAR in O muscles. Eukaryotic elongation factor 2 (eEF2) phosphorylation tended to be elevated in O vs. YA saline‐treated muscles, consistent with our previous results in rats. Since increased S6k activity would promote decreased eEF2 phosphorylation, any age‐related increase in eEF2 phosphorylation would be due to other factors besides S6k. In conclusion, chronic AICAR treatment in old mice reverses the age‐related change in resting mTOR pathway signaling that is observed in O skeletal muscle. This suggests that AMPK activation is a potential strategy for rescuing autophagy and other processes adversely affected by mTOR hyperactivation.Support or Funding InformationThis work was supported by an internal Gerontology Program Grant from Brigham Young University.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.