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 (α1/α2, β1/β2) or three (γ1/γ2/γ3) isoforms. Altered isoform composition affects AMPK localization and function. Previous work has shown that 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 α1 and α2 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 mo old) and old (O; 30 mo old) male Fischer344 x Brown Norway F1 hybrid rats after an in situ bout of endurance-type contractions produced via electrical stimulation of the sciatic nerve (STIM). AMPKα phosphorylation and AMPKα1 and α2 activities were unaffected by age at rest. However, AMPKα phosphorylation and AMPKα2 protein content and activity were lower in O vs. YA after STIM. Conversely, AMPKα1 content was greater in O vs. YA muscle, and α1 activity increased with STIM in O but not YA muscles. AMPKγ3 overall concentration and its association with AMPKα1 and α2 was lower in O vs. YA GAST. We conclude that activation of AMPKα1 is enhanced, while activation of α2 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 α1, α2 and γ3, this may contribute to sarcopenia and associated muscle metabolic dysfunction.
Many cell processes that are disrupted in aging skeletal muscle are also regulated by AMP‐activated protein kinase (AMPK). However, the effect of aging on skeletal muscle AMPK activation is controversial and unclear. Our purpose was to determine the effect of old‐age on endurance‐type contraction‐induced AMPK activation in skeletal muscle. Gastrocnemius muscles from YA (8 mo old) and O (30 mo old) male Fischer344 x Brown Norway F1 hybrid rats were removed after 10 minutes of electrically stimulated in situ contractions (STIM). Muscles from the resting legs served as controls (REST). AMPK phosphorylation and AMPKα2 activity were 63% and 19% lower, respectively, in O vs. YA muscles after STIM. AMPKα1 activity was unaffected by STIM in YA, but increased by 30% in O muscles. AMPK α1 protein concentration was 45% greater, while α2 content was 18% lower in O vs. YA muscles. AMPK β1, β2, and γ1 proteins were unaffected by age, but AMPK γ2 and γ3 concentrations were 75% and 85% lower in O vs. YA muscles, respectively. In conclusion, AMPKα2 activation is impaired while AMPKα1 activation is enhanced after endurance‐type in situ contractions in aged skeletal muscle. This work was funded by NIAMSD Grant AR‐51928.
AMP‐activated protein kinase (AMPK) is an important energy sensor in skeletal muscle. Many of the processes it regulates have been shown to be disrupted with aging. AMPK functions as heterotrimeric complex. The purpose of this study was to determine whether changes in the subunit composition of AMPK occur in aged skeletal muscle.. We studied gastrocnemius muscles from young adult (8 mo) and old (30 mo) male Fischer344 x Brown Norway F1 hybrid rats (n = 7–8/group). Immunoprecipitation (IP) of the catalytic AMPK α1 and α2 isoforms was followed by detection of associated β1, β2 and γ3 subunits by immunoblot. Protein levels for the β and γ isoforms were normalized to the corresponding α subunit with which they were immunoprecipitated. There was a 128% increase (p < 0.05) in the immunoprecipitated α1 subunit with age, accompanied by a 36% decrease in α2. There was a 59% decrease in β1 associated with α1 with age. No significant changes in β2 associated with α1, or in β1 or β2 associated with α2 were noted. AMPK γ3 association with α1 was decreased by 93% and with α2 by 83% with age. In conclusion, aging leads to a switch in AMPK subunit content and heterotrimer composition. Funding: NIAMSD Grant AR‐51928.
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