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

Abstract

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.

Increased Adenine Nucleotide Degradation in Skeletal Muscle Atrophy

“…Carefully designed and controlled animal aging studies have been instrumental for further identification of the age-related changes in the regulation of ATP and AdNs. Increased AdN degradation in aging skeletal muscle is supported by complementary reports of decreased [ATP] [140][141][142], reductions in the total AdN pool [143,144], and increased formation of purine degradation products such as hypoxanthine [145], and ammonia [146].…”

Piperine regulates UCP1 through the AMPK pathway by generating intracellular lactate production in muscle cells

“…AMP-activated protein kinase (AMPK), an energy sensor and master regulator of metabolic homeostasis, acts to increases glucose uptake, fatty acid oxidation, and mitochondrial biogenesis, all of which ameliorate insulin resistance45. AMPK is a heterotrimeric protein composed of α, β, and γ subunits; there are two isoforms each of α (α1 and α2) and β (β1 and β2) and three of γ (γ1, γ2, and γ3)6. An increased AMP:ATP ratio activates phosphorylation of Thr172 in the activation loop of the α subunit catalytic domain, enabling AMPK catalytic activity7.…”

AICAR and nicotinamide treatment synergistically augment the proliferation and attenuate senescence-associated changes in mesenchymal stromal cells

“…Furthermore, it increases the functionality of mitochondria and decreases ROS production by damaged mitochondria. These sequence of events prevents the MSCs to age and to show senescence-associated changes like dysfunctional autophagosome accumulation, and enlarged and flattened morphology upstream kinases on this residue [49,51,58,63]. One explanation would be the age-related mitochondrial defects, leading to a gradual disturbance of energy balance and AMP level [48,49].…”