AMP-activated protein kinase response to contractions and treatment with the AMPK activator AICAR in young adult and old skeletal muscle.
One characteristic of ageing skeletal muscle is a decline in mitochondrial function. Activation of AMP-activated protein kinase (AMPK) occurs in response to an increased AMP/ATP ratio, which is one potential result of mitochondrial dysfunction. We have previously observed higher AMPK activity in old (O; 30 months) vs young adult (YA; 8 months) fast-twitch muscle in response to chronic overload. Here we tested the hypothesis that AMPK would also be hyperactivated in O vs YA fast-twitch extensor digitorum longus muscles from Fischer(344) x Brown Norway (FBN) rats (n = 8 per group) in response to high-frequency electrical stimulation of the sciatic nerve (HFES) or injection of AICAR, an activator of AMPK. Muscles were harvested immediately after HFES (10 sets of six 3-s contractions, 10 s rest between contractions, 1 min rest between sets) or 1 h after AICAR injection (1 mg (g body weight)(-1) subcutaneously). The phosphorylations of AMPKalpha and acetyl-CoA carboxylase (ACC2; a downstream AMPK target) were both greatly increased (P <or= 0.05) in response to HFES in O muscles, but were either unresponsive (AMPK alpha) or much less responsive (ACC) in YA muscles. AMPK alpha2 activity was also greatly elevated in response to HFES in O muscles (but not YA muscles) despite a lower total AMPK alpha2 protein content in O vs YA muscles. In contrast, AMPK alpha2 activity was equally responsive to AICAR treatment in both age groups. Since mitochondrial content and/or efficiency could potentially underlie AMPK hyperactivation, we measured levels of mitochondrial proteins as well as citrate synthase (CS) activity. While CS activity was increased by 25% in O vs YA muscles, uncoupling protein-3 (UCP-3) protein level was upregulated with age by 353%. Thus, AMPK hyperactivation in response to contractile activity in aged fast-twitch muscle may be the result of compromised cellular energetics and not necessarily due to an inherent defect in responsiveness of the AMPK molecule per se.
Thomson
D M
DM
Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA. david_thomson@byu.edu
Brown
J D
JD
Fillmore
N
N
Ellsworth
S K
SK
Jacobs
D L
DL
Winder
W W
WW
Fick
C A
CA
Gordon
S E
SE
D055372:AMP-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism*; D000375:Aging / Q000187:drug effects / Q000502:physiology*; D000620:Aminoimidazole Carboxamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D012265:Ribonucleotides / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide