AMP-activated protein kinase (AMPK), a metabolic regulator, acts in opposition to many of the effects of aging and may provide insights into the development of sarcopenia. However, the effect of aging on AMPK activation is unclear. The purpose of this dissertation was to: 1) clarify the controversy concerning the activation of AMPK in response to endurance-like exercise in aged skeletal muscle; 2) address mechanisms for the age-associated alterations in AMPK activation; and 3) address the known benefits of chronic AICAR treatment in aged skeletal muscle. First, to clarify the effect of age on AMPK activation, young adult (YA) (8 mo.) and old (O) (30 mo.) male Fischer344 x Brown Norway F1 hybrid rats received an in situ bout of endurance-type contractions produced via electrical stimulation of the sciatic nerve (STIM). AMPK activation was attenuated in aging muscle as demonstrated by decreased AMPKα phosphorylation and AMPKα2 protein content and activity in O vs. YA muscle after STIM. In contrast, AMPKα1 content was greater in O vs. YA muscle, and α1 activity increased with STIM in O but not YA muscles. Second, the effect of age on the AMPK heterotrimer composition and nuclear localization was assessed as mechanisms for the altered AMPK activation. The AMPK heterotrimer composition was altered in aging skeletal muscle with lower AMPKγ2 and γ3 content and decreased association of AMPKγ3 with AMPKα1 and α2. Furthermore, activation of AMPK is known to increase translocation of AMPK to the nucleus in YA muscle; however, translocation of phosphorylated AMPK, AMPKα2, and AMPKγ3 were impaired in the aging rat muscle after STIM. Finally, chronic activation of AMPK with 5'-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) is known to increase mitochondrial content, activate autophagy, and repress protein synthesis; pathways that are altered with aging. The known benefits of chronic AICAR treatment were assessed in YA (5 mo.) and O (23 mo.) male C57Bl/6 mice. Mice were treadmill tested prior to and after one month of AICAR treatment. In vitro muscle contractions were performed following AICAR treatment. AICAR treatment improved the O mice treadmill endurance and the YA mice rate of fatigue and recovery. Additionally, AICAR increased citrate synthase activity, decreased SQSTM1/p62 protein content , and decreased Myf6 protein content in both the YA and O mice suggesting increased mitochondrial activity, autophagy, and decreased muscle regeneration. Therefore, chronic AICAR treatment may alter metabolic pathways to improve the exercise response in both YA and O mice.



College and Department

Life Sciences; Physiology and Developmental Biology



Date Submitted


Document Type





AMPK, aging, skeletal muscle, heterotrimer, AICAR, metabolism