Gene/Protein Disease Symptom Drug Enzyme Compound
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Regulation of protein translation through Akt and the downstream mammalian target of rapamycin (mTOR) pathway is an important component of the cellular response to hypertrophic stimuli. It has been proposed that 5'-AMP-activated protein kinase (AMPK) activation during muscle contraction may limit the hypertrophic response to resistance-type exercise by inhibiting translational signaling. However, experimental manipulation of AMPK activity during such a stimulus has not been attempted. Therefore, we investigated whether AMPK activation can attenuate the downstream signaling response of the Akt/mTOR pathway to electrically stimulated lengthening muscle contractions. Extensor digitorum longus muscles (n = 8/group) were subjected to a 22-min bout of lengthening contractions by high-frequency sciatic nerve electrical stimulation (STIM) in young adult (8 mo) Fischer 344 x Brown Norway male rats. Forty minutes before electrical stimulation, rats were subcutaneously injected with saline or 5-aminoimidazole-4-carboxamide-1-4-ribofuranoside (AICAR; 1 mg/g body wt), an AMPK activator. Stimulated and contralateral resting muscles were removed at 0, 20, and 40 min post-STIM, and AMPK, acetyl CoA carboxylase (ACC), Akt, eukaryotic initiation factor 4E-binding protein (4E-BP1), 70-kDa ribosomal protein S6 kinase (S6K1), and eukaryotic elongation factor 2 (eEF2) phosphorylations were assessed by Western blot. AICAR treatment increased (P < or = 0.05) post-STIM AMPK (Thr172) and ACC phosphorylation (Ser79/221), inhibited post-STIM S6K1 (Thr389) and 4E-BP1 (gel shift) phosphorylation, and elevated post-STIM eEF2 phosphorylation (Thr56). These findings suggest that translational signaling downstream of Akt/mTOR can be inhibited after lengthening contractions when preceded by AMPK activation and that energetic stress may be antagonistic to the hypertrophic translational signaling response to loaded muscle contractions.
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PMID:AMPK activation attenuates S6K1, 4E-BP1, and eEF2 signaling responses to high-frequency electrically stimulated skeletal muscle contractions. 1818 10

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.
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PMID:AMP-activated protein kinase response to contractions and treatment with the AMPK activator AICAR in young adult and old skeletal muscle. 1927 78

Evidence accumulations models (EAMs) have become the dominant modeling framework within rapid decision-making, using choice response time distributions to make inferences about the underlying decision process. These models are often applied to empirical data as "measurement tools", with different theoretical accounts being contrasted within the framework of the model. Some method is then needed to decide between these competing theoretical accounts, as only assessing the models on their ability to fit trends in the empirical data ignores model flexibility, and therefore, creates a bias towards more flexible models. However, there is no objectively optimal method to select between models, with methods varying in both their computational tractability and theoretical basis. I provide a systematic comparison between nine different model selection methods using a popular EAM-the linear ballistic accumulator (LBA; Brown & Heathcote, Cognitive Psychology 57(3), 153-178 2008)-in a large-scale simulation study and the empirical data of Dutilh et al. (Psychonomic Bulletin and Review, 1-19 2018). I find that the "predictive accuracy" class of methods (i.e., the Akaike Information Criterion [AIC], the Deviance Information Criterion [DIC], and the Widely Applicable Information Criterion [WAIC]) make different inferences to the "Bayes factor" class of methods (i.e., the Bayesian Information Criterion [BIC], and Bayes factors) in many, but not all, instances, and that the simpler methods (i.e., AIC and BIC) make inferences that are highly consistent with their more complex counterparts. These findings suggest that researchers should be able to use simpler "parameter counting" methods when applying the LBA and be confident in their inferences, but that researchers need to carefully consider and justify the general class of model selection method that they use, as different classes of methods often result in different inferences.
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PMID:Assessing the practical differences between model selection methods in inferences about choice response time tasks. 3078 96