The effects of age and muscle contraction on AMPK activity and heterotrimer composition

Sarcopenia is characterized by increased skeletal muscle atrophy due in part to alterations in muscle metabolism. AMP-activated protein kinase (AMPK) is a master regulator of skeletal muscle metabolic pathways which regulate many cellular processes that are disrupted in old-age. Functional AMPK is a heterotrimer composed of alpha, beta and gamma subunits, and each subunit can be represented in the heterotrimer by one of two (alpha 1/ alpha 2, beta 1/ beta 2) or three (gamma 1/gamma 2/gamma 3) isoforms. Altered isoform composition affects AMPK localization and function. Previous work has shownthat overall AMPK activation with endurance-type exercise is blunted in old vs. young skeletal muscle. However, details regarding the activation of the specific isoforms of AMPK, as well as the heterotrimeric composition of AMPK in old skeletal muscle, are unknown. Our purpose here, therefore, was to determine the effect of old-age on 1) the activation of the alpha 1 and alpha 2 catalytic subunits of AMPK in skeletal muscle by a continuous contraction bout, and 2) the heterotrimeric composition of skeletal muscle AMPK. We studied gastrocnemius (GAST) and tibialis anterior (TA) muscles from young adult (YA; 8 months old) and old (O; 30 months old) male Fischer(344) x Brown Norway F1 hybrid rats after an in situ bout of endurance-type contractions produced via electrical stimulation of the sciatic nerve (STIM). AMPK alpha phosphorylation and AMPK alpha 1 and alpha 2 activities were unaffected by age at rest. However, AMPK alpha phosphorylation and AMPK alpha 2 protein content and activity were lower in O vs. YA after STIM. Conversely, AMPK alpha 1 content was greater in O vs. YA muscle, and alpha 1 activity increased with STIM in O but not YA muscles. AMPK gamma 3 overall concentration and its association with AMPK alpha 1 and alpha 2 were lower in O vs. YA GAST. We conclude that activation of AMPK alpha 1 is enhanced, while activation of a2 is suppressed immediately after repeated skeletal muscle contractions in O vs. YA skeletal muscle. These changes are associated with changes in the AMPK heterotrimer composition. Given the known roles of AMPK alpha 1, alpha 2 and gamma 3, this may contribute to sarcopenia and associated muscle metabolic dysfunction. (C) 2014 Elsevier Inc. All rights reserved.