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Biomedical subjects

Erik A Richter

Publications and source records attributed to Erik A Richter.

At least 19 recordsLinked to original sources
PubMed2007

Possible CaMKK-dependent regulation of AMPK phosphorylation and glucose uptake at the onset of mild tetanic skeletal muscle contraction.

The Ca(2+)/calmodulin (CaM) competitive inhibitor KN-93 has previously been used to evaluate 5'-AMP-activated protein kinase (AMPK)-independent Ca(2+)-signaling to contraction-stimulated glucose uptake in muscle during intense electrical stimulation ex vivo. With the use of low-intensity tetanic contraction of mouse soleus and extensor digitorum longus (EDL) muscles ex vivo, this study demonstrates that KN-93 can potently inhibit AMPK phosphorylation and activity after 2 min but not 10 min of contraction while strongly inhibiting contraction-stimulated 2-deoxyglucose uptake at both the 2- and 10-min time points. These data suggest inhibition of Ca(2+)/CaM-dependent signaling events upstream of AMPK, the most likely candidate being the novel AMPK kinase CaM-dependent protein kinase kinase (CaMKK). CaMKK protein expression was detected in mouse skeletal muscle. Similar to KN-93, the CaMKK inhibitor STO-609 strongly reduced AMPK phosphorylation and activity at 2 min and less potently at 10 min. Pretreatment with STO-609 inhibited contraction-stimulated glucose uptake at 2 min in soleus, but not EDL, and in both muscles after 10 min. Neither KN-93 nor STO-609 inhibited 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside-stimulated glucose uptake, AMPK phosphorylation, or recombinant LKB1 activity, suggestive of an LKB1-independent effect. Finally, neither KN-93 nor STO-609 had effects on the reductions in glucose uptake seen in mice overexpressing a kinase-dead AMPK construct, indicating that the effects of KN-93 and STO-609 on glucose uptake require inhibition of AMPK activity. We propose that CaMKKs act in mouse skeletal muscle regulating AMPK phosphorylation and glucose uptake at the onset of mild tetanic contraction and that an intensity- and/or time-dependent switch occurs in the relative importance of AMPKKs during contraction.

AMP-Activated Protein Kinase Kinases↗
PubMed2006

AS160 phosphorylation is associated with activation of alpha2beta2gamma1- but not alpha2beta2gamma3-AMPK trimeric complex in skeletal muscle during exercise in humans.

We investigated time- and intensity-dependent effects of exercise on phosphorylation of Akt substrate of 160 kDa (AS160) in human skeletal muscle. Subjects performed cycle exercise for 90 min (67% VO2 peak, n=8), 20 min (80% VO2 peak, n=11), 2 min (110% of peak work rate, n=9), or 30 s (maximal sprint, n=10). Muscle biopsies were obtained before, during, and after exercise. In trial 1, AS160 phosphorylation increased at 60 min (60%, P=0.06) and further at 90 min of exercise (120%, P<0.05). alpha2beta2gamma3-AMP-activated protein kinase (AMPK) activity increased significantly to a steady-state level after 30 min, whereas alpha2beta2gamma1-AMPK activity increased after 60 min of exercise with a further significant increase after 90 min. alpha2beta2gamma1-AMPK activity and AS160 phosphorylation correlated positively (r2=0.55). In exercise trials 2, 3, and 4, alpha2beta2gamma3-AMPK activity but neither AS160 phosphorylation nor alpha2beta2gamma1-AMPK activity increased. Akt Ser473 phosphorylation was unchanged in all trials, whereas Akt Thr308 phosphorylation increased significantly in trial 3 and 4 only. These results show that AS160 is phosphorylated in a time-dependent manner during moderate-intensity exercise and suggest that alpha2beta2gamma1- but not alpha2beta2gamma3-AMPK may act in a pathway responsible for exercise-induced AS160 phosphorylation. Furthermore, we show that AMPK complexes in skeletal muscle are activated differently depending on exercise intensity and duration.

AMP-Activated Protein Kinases↗
PubMed2006

Role of AMPKalpha2 in basal, training-, and AICAR-induced GLUT4, hexokinase II, and mitochondrial protein expression in mouse muscle.

We investigated the role of AMPKalpha2in basal, exercise training-, and AICAR-induced protein expression of GLUT4, hexokinase II (HKII), mitochondrial markers, and AMPK subunits. This was conducted in red (RG) and white gastrocnemius (WG) muscle from wild-type (WT) and alpha2-knockout (KO) mice after 28 days of activity wheel running or daily AICAR injection. Additional experiments were conducted to measure acute activation of AMPK by exercise and AICAR. At basal, mitochondrial markers were reduced by approximately 20% in alpha2-KO muscles compared with WT. In both muscle types, AMPKalpha2 activity was increased in response to both stimuli, whereas AMPKalpha1 activity was increased only in response to exercise. Furthermore, AMPK signaling was estimated to be 60-70% lower in alpha2-KO compared with WT muscles. In WG, AICAR treatment increased HKII, GLUT4, cytochrome c, COX-1, and CS, and the alpha2-KO abolished the AICAR-induced increases, whereas no AICAR responses were observed in RG. Exercise training increased GLUT4, HKII, COX-1, CS, and HAD protein in WG, but the alpha2-KO did not affect training-induced increases. Furthermore, AMPKalpha1, -alpha2, -beta1, -beta2, and -gamma3 subunits were reduced in RG, but not in WG, by 30-60% in response to exercise training. In conclusion, the alpha2-KO was associated with an approximately 20% reduction in mitochondrial markers in both muscle types and abolished AICAR-induced increases in protein expression in WG. However, the alpha2-KO did not reduce training-induced increases in HKII, GLUT4, COX-1, HAD, or CS protein in WG, suggesting that AMPKalpha2 may not be essential for metabolic adaptations of skeletal muscles to exercise training.

AMP-Activated Protein Kinases↗
PubMed2006

Role of AMPK in skeletal muscle metabolic regulation and adaptation in relation to exercise.

The 5'-AMP-activated protein kinase (AMPK) is a potent regulator of skeletal muscle metabolism and gene expression. AMPK is activated both in response to in vivo exercise and ex vivo contraction. AMPK is therefore believed to be an important signalling molecule in regulating muscle metabolism during exercise as well as in adaptation of skeletal muscle to exercise training. The first part of this review is focused on different mechanisms regulating AMPK activity during muscle work such as alterations in nucleotide concentrations, availability of energy substrates and upstream AMPK kinases. We furthermore discuss the possible role of AMPK as a master switch in skeletal muscle metabolism with the main focus on AMPK in metabolic regulation during muscle work. Finally, AMPK has a well established role in regulating expression of genes encoding various enzymes in muscle, and this issue is discussed in relation to adaptation of skeletal muscle to exercise training.

AMP-Activated Protein Kinases↗
PubMed2006

Ca2+-calmodulin-dependent protein kinase expression and signalling in skeletal muscle during exercise.

Ca2+ signalling is proposed to play an important role in skeletal muscle function during exercise. Here, we examined the expression of multifunctional Ca2+-calmodulin-dependent protein kinases (CaMK) in human skeletal muscle and show that CaMKII and CaMKK, but not CaMKI or CaMKIV, are expressed. Furthermore, the effect of exercise duration and intensity on skeletal muscle CaMKII activity and phosphorylation of downstream targets was examined. Eight healthy men exercised at approximately 67% of peak pulmonary O2 uptake(VO2peak) with muscle samples taken at rest and after 1, 10, 30, 60 and 90 min of exercise. Ten other men exercised for three consecutive 10 min bouts at 35%, 60% and 85% VO2peak with muscle samples taken at rest, at the end of each interval and 30 min post-exercise. There was a rapid and transient increase in autonomous CaMKII activity and CaMKII phosphorylation at Thr287 in skeletal muscle during exercise. Furthermore, the phosphorylation of phospholamban (PLN) at Thr17, which was identified as a CaMKII substrate in skeletal muscle, was rapidly (< 1 min) increased by exercise, and remained phosphorylated 5-fold above basal level during 90 min of exercise. The phosphorylation of serum response factor at Ser103, a putative CaMKII substrate, was higher after 30 min of exercise. PLN phosphorylation at Thr17 was higher with increasing exercise intensities. These data indicate that CaMKII is the major multifunctional CaMK in skeletal muscle and its activation occurs rapidly and is sustained during continuous exercise, with the activation being greater during intense exercise.

Adult↗
PubMed2006

Higher skeletal muscle alpha2AMPK activation and lower energy charge and fat oxidation in men than in women during submaximal exercise.

5'AMP-activated protein kinase (AMPK) is an energy sensor activated by perturbed cellular energy status such as during muscle contraction. Activated AMPK is thought to regulate several key metabolic pathways. We used sex comparison to investigate whether AMPK signalling in skeletal muscle regulates fat oxidation during exercise. Moderately trained women and men completed 90 min bicycle exercise at 60% VO2peak. Both AMPK Thr172 phosphorylation and alpha2AMPK activity were increased by exercise in men (approximately 200%, P < 0.001) but not significantly in women. The sex difference in muscle AMPK activation with exercise was accompanied by an increase in muscle free AMP (approximately 164%, P < 0.01), free AMP/ATP ratio (159%, P < 0.05), and creatine (approximately 42%, P < 0.001) in men but not in women (NS), suggesting that lack of AMPK activation in women was due to better maintenance of muscle cellular energy balance compared with men. During exercise, fat oxidation per kg lean body mass was higher in women than in men (P < 0.05). Regression analysis revealed that a higher proportion of type 1 muscle fibres (approximately 23%, P < 0.01) and a higher capillarization (approximately 23%, P < 0.05) in women than in men could partly explain the sex difference in alpha2AMPK activity (r = -0.54, P < 0.05) and fat oxidation (r = 0.64, P < 0.05) during exercise. On the other hand, fat oxidation appeared not to be regulated via AMPK. In conclusion, during prolonged submaximal exercise at 60% VO2peak, higher fat oxidation in women cannot be explained by higher AMPK signalling but is accompanied by improved muscle cellular energy balance in women probably due to sex specific muscle morphology.

AMP-Activated Protein Kinases↗
PubMed2006

[5'-adenosine monophosphate-activated protein kinase and lifestyle-mediated diseases].

5'-adenosine monophosphate-activated protein kinase (AMPK) is an enzyme activated when cellular energy status is threatened. AMPK activates energy-providing processes, while energy-consuming processes are inhibited. AMPK is also involved in regulation of gene expression and in appetite control. Pharmacological activation of AMPK in animal models of the metabolic syndrome leads to marked amelioration of symptoms. Some antidiabetic drugs activate AMPK, and activation also occurs during physical exercise. It is likely that part of the effect of physical activity in preventing the development of diseases related to a sedentary lifestyle is due to activation of AMPK.

AMP-Activated Protein Kinases↗
PubMed2006

Effects of acute exercise and training on insulin action and sensitivity: focus on molecular mechanisms in muscle.

A single bout of exercise increases insulin sensitivity for several hours and the effect is mainly restricted to the muscles recruited during exercise. When exercise is repeated over time, adaptations to physical training occur that include more long-lasting increases in insulin sensitivity. The present review explores the molecular mechanisms involved in both the acute and chronic effects of exercise on insulin sensitivity in skeletal muscle.

Animals↗
PubMed2006

AMPK-mediated AS160 phosphorylation in skeletal muscle is dependent on AMPK catalytic and regulatory subunits.

AMP-activated protein kinase (AMPK) is a heterotrimeric protein that regulates glucose transport mediated by cellular stress or pharmacological agonists such as 5-aminoimidazole-4-carboxamide 1 beta-d-ribonucleoside (AICAR). AS160, a Rab GTPase-activating protein, provides a mechanism linking AMPK signaling to glucose uptake. We show that AICAR increases AMPK, acetyl-CoA carboxylase, and AS160 phosphorylation by insulin-independent mechanisms in isolated skeletal muscle. Recombinant AMPK heterotrimeric complexes (alpha1beta1gamma1 and alpha2beta2gamma1) phosphorylate AS160 in a cell-free assay. In mice deficient in AMPK signaling (alpha2 AMPK knockout [KO], alpha2 AMPK kinase dead [KD], and gamma3 AMPK KO), AICAR effects on AS160 phosphorylation were severely blunted, highlighting that complexes containing alpha2 and gamma3 are necessary for AICAR-stimulated AS160 phosphorylation in intact skeletal muscle. Contraction-mediated AS160 phosphorylation was also impaired in alpha2 AMPK KO and KD but not gamma3 AMPK KO mice. Our results implicate AS160 as a downstream target of AMPK.

Adenylate Kinase↗
PubMed2005

Exercise rapidly increases eukaryotic elongation factor 2 phosphorylation in skeletal muscle of men.

Protein synthesis in skeletal muscle is known to decrease during contractions but the underlying regulatory mechanisms are unknown. Here, the effect of exercise on skeletal muscle eukaryotic elongation factor 2 (eEF2) phosphorylation, a key component in protein translation machinery, was examined. Eight healthy men exercised on a cycle ergometer at a workload eliciting approximately 67% peak pulmonary oxygen consumption (VO2 peak) with skeletal muscle biopsies taken from the vastus lateralis muscle at rest as well as after 1, 10, 30, 60 and 90 min of exercise. In response to exercise, there was a rapid (i.e. < 1 min) 5- to 7-fold increase in eEF2 phosphorylation at Thr56 that was sustained for 90 min of continuous exercise. The in vitro activity of skeletal muscle eEF2 kinase was not altered by exercise indicating that the increased activity of eEF2 kinase to eEF2 is not mediated by covalent mechanisms. In support of this, the increase in AMPK activity was temporally unrelated to eEF2 phosphorylation. However, skeletal muscle eEF2 kinase was potently activated by Ca(2)(+)-calmodulin in vitro, suggesting that the higher eEF2 phosphorylation in working skeletal muscle is mediated by allosteric activation of eEF2 kinase by Ca(2)(+) signalling via calmodulin. Given that eEF2 phosphorylation inhibits eEF2 activity and mRNA translation, these findings suggest that the inhibition of protein synthesis in contracting skeletal muscle is due to the Ca(2)(+)-induced stimulation of eEF2 kinase.

Adult↗
PubMed2005

The effect of caffeine on glucose kinetics in humans--influence of adrenaline.

While caffeine impedes insulin-mediated glucose disposal in humans, its effect on endo-genous glucose production (EGP) remains unknown. In addition, the mechanism involved in these effects is unclear, but may be due to the accompanying increase in adrenaline concentration. We studied the effect of caffeine on EGP and glucose infusion rates (GIR), and whether or not adrenaline can account for all of caffeine's effects. Subjects completed three isoglycaemic-hyperinsulinaemic clamps (with 3-[(3)H]glucose infusion) 30 min after ingesting: (1) placebo capsules (n= 12); (2) caffeine capsules (5 mg kg(-1)) (n= 12); and either (3) placebo plus a high-dose adrenaline infusion (HAdr; adrenaline concentration, 1.2 nM; n= 8) or (4) placebo plus a low-dose adrenaline infusion (LAdr; adrenaline concentration, 0.75 nM; n= 6). With caffeine, adrenaline increased to 0.6 nM but no effect on EGP was observed. While caffeine and HAdr decreased GIR by 13 (P < 0.05) and 34% (P < 0.05) versus the placebo, respectively, LAdr did not result in a significant reduction (5%) in GIR versus the placebo. Due to the fact that both caffeine and LAdr resulted in similar adrenaline concentrations, but resulted in different decreases in GIR, it is concluded that adrenaline alone does not account for the effects of caffeine and additional mechanisms must be involved.

Administration, Oral↗
PubMed2005

Effects of alpha-AMPK knockout on exercise-induced gene activation in mouse skeletal muscle.

We tested the hypothesis that 5'AMP-activated protein kinase (AMPK) plays an important role in regulating the acute, exercise-induced activation of metabolic genes in skeletal muscle, which were dissected from whole-body alpha2- and alpha1-AMPK knockout (KO) and wild-type (WT) mice at rest, after treadmill running (90 min), and in recovery. Running increased alpha1-AMPK kinase activity, phosphorylation (P) of AMPK, and acetyl-CoA carboxylase (ACC)beta in alpha2-WT and alpha2-KO muscles and increased alpha2-AMPK kinase activity in alpha2-WT. In alpha2-KO muscles, AMPK-P and ACCbeta-P were markedly lower compared with alpha2-WT. However, in alpha1-WT and alpha1-KO muscles, AMPK-P and ACCbeta-P levels were identical at rest and increased similarly during exercise in the two genotypes. The alpha2-KO decreased peroxisome-proliferator-activated receptor gamma coactivator (PGC)-1alpha, uncoupling protein-3 (UCP3), and hexokinase II (HKII) transcription at rest but did not affect exercise-induced transcription. Exercise increased the mRNA content of PGC-1alpha, Forkhead box class O (FOXO)1, HKII, and pyruvate dehydrogenase kinase 4 (PDK4) similarly in alpha2-WT and alpha2-KO mice, whereas glucose transporter GLUT 4, carnitine palmitoyltransferase 1 (CPTI), lipoprotein lipase, and UCP3 mRNA were unchanged by exercise in both genotypes. CPTI mRNA was lower in alpha2-KO muscles than in alpha2-WT muscles at all time-points. In alpha1-WT and alpha1-KO muscles, running increased the mRNA content of PGC-1alpha and FOXO1 similarly. The alpha2-KO was associated with lower muscle adenosine 5'-triphosphate content, and the inosine monophosphate content increased substantially at the end of exercise only in alpha2-KO muscles. In addition, subcutaneous injection of 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) increased the mRNA content of PGC-1alpha, HKII, FOXO1, PDK4, and UCP3, and alpha2-KO abolished the AICAR-induced increases in PGC-1alpha and HKII mRNA. In conclusion, KO of the alpha2- but not the alpha1-AMPK isoform markedly diminished AMPK activation during running. Nevertheless, exercise-induced activation of the investigated genes in mouse skeletal muscle was not impaired in alpha1- or alpha2-AMPK KO muscles. Although it cannot be ruled out that activation of the remaining alpha-isoform is sufficient to increase gene activation during exercise, the present data do not support an essential role of AMPK in regulating exercise-induced gene activation in skeletal muscle.

AMP-Activated Protein Kinases↗
PubMed2005

Increases in glycogenin and glycogenin mRNA accompany glycogen resynthesis in human skeletal muscle.

Glycogenin is the self-glycosylating protein primer that initiates glycogen granule formation. To examine the role of this protein during glycogen resynthesis, eight male subjects exercised to exhaustion on a cycle ergometer at 75% Vo2 max followed by five 30-s sprints at maximal capacity to further deplete glycogen stores. During recovery, carbohydrate (75 g/h) was supplied to promote rapid glycogen repletion, and muscle biopsies were obtained from the vastus lateralis at 0, 30, 120, and 300 min postexercise. At time 0, no free (deglycosylated) glycogenin was detected in muscle, indicating that all glycogenin was complexed to carbohydrate. Glycogenin activity, a measure of the glycosylating ability of the protein, increased at 30 min and remained elevated for the remainder of the study. Quantitative RT-PCR showed elevated glycogenin mRNA at 120 min followed by increases in protein levels at 300 min. Glycogenin specific activity (glycogenin activity/relative protein content) was also elevated at 120 min. Proglycogen increased at all time points, with the highest rate of resynthesis occurring between 0 and 30 min. In comparison, macroglycogen levels did not significantly increase until 300 min postexercise. Together, these results show that, during recovery from prolonged exhaustive exercise, glycogenin mRNA and protein content and activity increase in muscle. This may facilitate rapid glycogen resynthesis by providing the glycogenin backbone of proglycogen, the major component of glycogen synthesized in early recovery.

Adult↗
PubMed2005

Glycogenin activity and mRNA expression in response to volitional exhaustion in human skeletal muscle.

Glycogenolysis results in the selective catabolism of individual glycogen granules by glycogen phosphorylase. However, once the carbohydrate portion of the granule is metabolized, the fate of glycogenin, the protein primer of granule formation, is not known. To examine this, male subjects (n = 6) exercised to volitional exhaustion (Exh) on a cycle ergometer at 75% maximal O2 uptake. Muscle biopsies were obtained at rest, 30 min, and Exh (99 +/- 10 min). At rest, total glycogen concentration was 497 +/- 41 and declined to 378 +/- 51 mmol glucosyl units/kg dry wt following 30 min of exercise (P < 0.05). There were no significant changes in proglycogen, macroglycogen, glycogenin activity, or mRNA in this period (P > or = 0.05). Exh resulted in decreases in total glycogen, proglycogen, and macroglycogen as well as glycogenin activity (P < 0.05). These decrements were associated with a 1.9 +/- 0.4-fold increase in glycogenin mRNA over resting values (P < 0.05). Glycogenolysis in the initial exercise period (0-30 min) was not adequate to induce changes in glycogenin; however, later in exercise when concentration and granule number decreased further, decrements in glycogenin activity and increases in glycogenin mRNA were demonstrated. Results show that glycogenin becomes inactivated with glycogen catabolism and that this event coincides with an increase in glycogenin gene expression as exercise and glycogenolysis progress.

Adult↗
PubMed2005

Exercise in rats does not alter hypothalamic AMP-activated protein kinase activity.

Recent studies have demonstrated that AMP-activated protein kinase (AMPK) in the hypothalamus is involved in the regulation of food intake. Because exercise is known to influence appetite and cause substrate depletion, it may also influence AMPK in the hypothalamus. Male rats that either rested or ran for 30 or 60 min on a treadmill (22 m/min, 10% slope) were sacrificed immediately after exercise or after 60 min recovery either in the fasted state or after oral gavage with glucose (3g/kg body weight). Exercise decreased muscle and liver glycogen substantially. Hypothalamic total or alpha2-associated AMPK activity and phosphorylation state of the AMPK substrate acetyl-CoA carboxylase were not changed significantly immediately following treadmill running or during fed or fasted recovery. Plasma ghrelin increased (P<0.05) by 40% during exercise whereas the concentration of PYY was unchanged. In recovery, glucose feeding increased plasma glucose and insulin concentrations whereas ghrelin and PYY decreased to (ghrelin) or below (PPY) resting levels. It is concluded that 1h of strenuous exercise in rats does not elicit significant changes in hypothalamic AMPK activity despite an increase in plasma ghrelin. Thus, changes in energy metabolism during or after exercise are likely not coordinated by changes in hypothalamic AMPK activity.

AMP-Activated Protein Kinases↗
PubMed2005

Skeletal muscle glucose uptake during exercise: how is it regulated?

The increase in skeletal muscle glucose uptake during exercise results from a coordinated increase in rates of glucose delivery (higher capillary perfusion), surface membrane glucose transport, and intracellular substrate flux through glycolysis. The mechanism behind the movement of GLUT4 to surface membranes and the subsequent increase in transport by muscle contractions is largely unresolved, but it is likely to occur through intracellular signaling involving Ca(2+)-calmodulin-dependent protein kinase, 5'-AMP-activated protein kinase, and possibly protein kinase C.

Animals↗
PubMed2005

Impact of genetic versus environmental factors on the control of muscle glycogen synthase activation in twins.

Storage of glucose as glycogen accounts for the largest proportion of muscle glucose metabolism during insulin infusion in normal and insulin-resistant subjects. Studies in first-degree relatives have indicated a genetic origin of the defective insulin activation of muscle glycogen synthase (GS) in type 2 diabetes. The aim of this study was to evaluate the relative impact of genetic versus nongenetic factors on muscle GS activation and regulation in young and elderly twins examined with a 2-h euglycemic-hyperinsulinemic (40 mU x m(-2) x min(-1)) clamp combined with indirect calorimetry and excision of muscle biopsies. The etiological components were determined using structural equation modeling. Fractional GS activity; GS phosphorylation at sites 2, 2 + 2a, and 3a + 3b corrected for total GS protein; and GS kinase 3 (GSK3) activity were similar in both age groups, whereas total GS activity and protein were lower in elderly compared with younger twins. GS fractional activity increased significantly during insulin stimulation in both young and elderly twins. Conversely, there was a significant decrease in GS phosphorylation at site 3a + 3b and GSK3 activity during insulin stimulation in both age groups, whereas GS phosphorylation at site 2 and 2 + 2a only decreased on insulin stimulation in the younger twins. The increment in whole-body glucose disposal (Rd) and nonoxidative glucose metabolism (insulin - basal) correlated significantly with the increment in GS fractional activity. Fractional GS activity had a major environmental component in both age groups. GSK3 activity exhibited a genetic component in young (basal: a2 = 0.42; insulin: a2 = 0.58) and elderly (insulin: a2 = 0.56) twins. Furthermore, GS phosphorylation at site 2 (insulin: a2 = 0.69) in the elderly and at site 3a + 3b (insulin: a2 = 0.50) in the young twins had a genetic component. In conclusion, GSK3 activity and GS phosphorylation, particularly at sites 2 and 3a + 3b, had major genetic components. Total and fractional GS activities per se were, on the other hand, predominantly controlled by environmental factors. Moreover, GS activity was intact with increasing age, despite a significant reduction in nonoxidative glucose metabolism.

Adult↗