Regulation of skeletal muscle carbohydrate oxidation during steady-state contraction

1998 ◽  
Vol 274 (5) ◽  
pp. R1384-R1389 ◽  
Author(s):  
James A. Timmons ◽  
Simon M. Poucher ◽  
Dumitru Constantin-Teodosiu ◽  
Ian A. Macdonald ◽  
Paul L. Greenhaff
Keyword(s):  
Skeletal Muscle ◽  
Steady State ◽  
Pyruvate Dehydrogenase Complex ◽  
Substrate Oxidation ◽  
Carbohydrate Oxidation ◽  
Control Group ◽  
Acetyl Coa ◽  
Glucose Fatty Acid Cycle ◽  
State Contraction ◽  
Activation Status

Pyruvate dehydrogenase complex (PDC) activation status has been described as being central in the regulation of tissue substrate oxidation as outlined by the glucose fatty-acid cycle. In the present study we examined the effects of reduced lipolysis, with use of nicotinate, and increased PDC activation, with use of dichloroacetate (DCA), on substrate utilization during 20 min of submaximal steady-state contraction (∼80% of maximal O2uptake) in canine gracilis skeletal muscle. At rest, PDC activation was unchanged by nicotinate but was ∼2.5-fold higher in the DCA group than in the control group ( P < 0.05). During contraction, PDC activation status increased to 3.5 mmol acetyl-CoA ⋅ min−1 ⋅ kg−1at 37°C in the control group, remained at 4.5 mmol acetyl-CoA ⋅ min−1 ⋅ kg−1at 37°C in the DCA group, but only increased to 2.2 mmol acetyl-CoA ⋅ min−1 ⋅ kg−1at 37°C in the nicotinate group ( P< 0.05). However, the estimated amount of carbohydrate oxidized during the 20-min contraction was similar across groups and did not follow the degree of PDC activation (81.2 ± 22.9, 95.9 ± 11.7, and 89.3 ± 18.9 mmol glucosyl units/kg dry muscle for control, nicotinate, and DCA, respectively). Thus it would appear that, during steady-state contraction, PDC activation status does not determine the rate of carbohydrate oxidation in skeletal muscle.

Metabolic responses from rest to steady state determine contractile function in ischemic skeletal muscle

1997 ◽  
Vol 273 (2) ◽  
pp. E233-E238 ◽  
Author(s):  
J. A. Timmons ◽  
S. M. Poucher ◽  
D. Constantin-Teodosiu ◽  
I. A. Macdonald ◽  
P. L. Greenhaff
Keyword(s):  
Skeletal Muscle ◽  
Steady State ◽  
Muscle Contraction ◽  
Metabolic Response ◽  
Contractile Function ◽  
Pyruvate Dehydrogenase Complex ◽  
Force Production ◽  
Critical Factor ◽  
Control Group ◽  
State Force

Skeletal muscle contraction during ischemia, such as that experienced by peripheral vascular disease patients, is characterized by rapid fatigue. Using a canine gracilis model, we tested the hypothesis that a critical factor determining force production during ischemia is the metabolic response during the transition from rest to steady state. Dichloroacetate (DCA) administration before gracilis muscle contraction increased pyruvate dehydrogenase complex activation and resulted in acetylation of 80% of the free carnitine pool to acetylcarnitine. After 1 min of contraction, phosphocreatine (PCr) degradation in the DCA group was approximately 50% lower than in the control group (P < 0.05) during conditions of identical force production. After 6 min of contraction, steady-state force production was approximately 30% higher in the DCA group (P < 0.05), and muscle ATP, PCr, and glycogen degradation and lactate accumulation were lower (P < 0.05 in all cases). It appears, therefore, that an important determinant of contractile function during ischemia is the mechanisms by which ATP regeneration occurs during the period of rest to steady-state transition.

Skeletal muscle pyruvate dehydrogenase activity during acetate infusion in humans

1995 ◽  
Vol 268 (5) ◽  
pp. E1007-E1017 ◽  
Author(s):  
C. T. Putman ◽  
L. L. Spriet ◽  
E. Hultman ◽  
D. J. Dyck ◽  
G. J. Heigenhauser
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Dehydrogenase Activity ◽  
Pyruvate Dehydrogenase ◽  
Acetate Metabolism ◽  
Acetyl Coa ◽  
Acid Cycle ◽  
Citrate Accumulation ◽  
Acetyl Group ◽  
Glucose Fatty Acid Cycle

Pyruvate dehydrogenase activity (PDHa), acetyl group, and citrate accumulation were examined in human skeletal muscle at rest and during cycling exercise while acetate was infused. Eight subjects received 400 mmol of sodium acetate (Ace) at a constant rate during 20 min of rest, 5 min of cycling at 40% maximal O2 uptake (VO2max) and 15 min of cycling at 80% VO2max. Two weeks later experiments were repeated while 400 mmol of sodium bicarbonate was infused in the control condition (CON). Ace infusion increased muscle acetyl-coenzyme A (acetyl-CoA), citrate, and acetylcarnitine. A decline in resting PDHa during 20 min of Ace infusion (0.37 +/- 0.08 vs. 0.16 +/- 0.03 mmol.min-1.kg wet wt-1) coincided with an elevation in the acetyl-CoA-to-free CoA ratio (acetyl-CoA/CoASH; 0.28 +/- 0.04 to 0.73 +/- 0.14). After 20 min of CON infusion, resting PDHa (0.32 +/- 0.06 mmol.min-1.kg wet wt-1) was similar to PDHa before Ace infusion. During exercise, acetyl-CoA, citrate, and acetyl-CoA/CoASH were further elevated, and the differences that existed at rest were resolved. PDHa increased to the same extent in Ace and CON, in which it was 44-47% transformed after 5 min at 40% VO2max and completely transformed after 15 min at 80% VO2max. At rest PDHa was regulated by variations in acetyl-CoA/CoASH secondary to enhanced acetate metabolism. Conversely, during exercise PDHa regulation appeared independent of variations in acetyl-CoA/CoASH. The resting data are consistent with a central role for PDHa and citrate in the regulation of the glucose-fatty acid cycle in skeletal muscle, as classically proposed. However, in the present study Ace infusion was not effective in perturbing the glucose-fatty acid cycle during exercise.

Effects of hyperoxia on skeletal muscle carbohydrate metabolism during transient and steady-state exercise

2005 ◽  
Vol 98 (1) ◽  
pp. 250-256 ◽  
Author(s):  
Trent Stellingwerff ◽  
Lee Glazier ◽  
Matthew J. Watt ◽  
Paul J. LeBlanc ◽  
George J. F. Heigenhauser ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Steady State ◽  
Blood Lactate ◽  
Active Form ◽  
Carbohydrate Oxidation ◽  
Muscle Lactate ◽  
Carbohydrate Utilization ◽  
Lactate Accumulation ◽  
Substrate Phosphorylation ◽  
Blood Lactate Accumulation

This study compared the effects of inspiring either a hyperoxic (60% O2) or normoxic gas (21% O2) while cycling at 70% peak O2 uptake on 1) the ATP derived from substrate phosphorylation during the initial minute of exercise, as estimated from phosphocreatine degradation and lactate accumulation, and 2) the reliance on carbohydrate utilization and oxidation during steady-state cycling, as estimated from net muscle glycogen use and the activity of pyruvate dehydrogenase (PDH) in the active form (PDHa), respectively. We hypothesized that 60% O2 would decrease substrate phosphorylation at the onset of exercise and that it would not affect steady-state exercise PDH activity, and therefore muscle carbohydrate oxidation would be unaltered. Ten active male subjects cycled for 15 min on two occasions while inspiring 21% or 60% O2, balance N2. Blood was obtained throughout and skeletal muscle biopsies were sampled at rest and 1 and 15 min of exercise in each trial. The ATP derived from substrate-level phosphorylation during the initial minute of exercise was unaffected by hyperoxia (21%: 52.2 ± 11.1; 60%: 54.0 ± 9.5 mmol ATP/kg dry wt). Net glycogen breakdown during 15 min of cycling was reduced during the 60% O2 trial vs. 21% O2 (192.7 ± 25.3 vs. 138.6 ± 16.8 mmol glycosyl units/kg dry wt). Hyperoxia had no effect on PDHa, because it was similar to the 21% O2 trial at rest and during exercise (21%: 2.20 ± 0.26; 60%: 2.25 ± 0.30 mmol·kg wet wt−1·min−1). Blood lactate was lower (6.4 ± 1.0 vs. 8.9 ± 1.0 mM) at 15 min of exercise and net muscle lactate accumulation was reduced from 1 to 15 min of exercise in the 60% O2 trial compared with 21% (8.6 ± 5.1 vs. 27.3 ± 5.8 mmol/kg dry wt). We concluded that O2 availability did not limit oxidative phosphorylation in the initial minute of the normoxic trial, because substrate phosphorylation was unaffected by hyperoxia. Muscle glycogenolysis was reduced by hyperoxia during steady-state exercise, but carbohydrate oxidation (PDHa) was unaffected. This closer match between pyruvate production and oxidation during hyperoxia resulted in decreased muscle and blood lactate accumulation. The mechanism responsible for the decreased muscle glycogenolysis during hyperoxia in the present study is not clear.

Malonyl-CoA regulation in skeletal muscle: its link to cell citrate and the glucose-fatty acid cycle

1997 ◽  
Vol 272 (4) ◽  
pp. E641-E648 ◽  
Author(s):  
A. K. Saha ◽  
D. Vavvas ◽  
T. G. Kurowski ◽  
A. Apazidis ◽  
L. A. Witters ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Pancreatic Beta Cell ◽  
Acid Oxidation ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Acid Cycle ◽  
Citrate Lyase ◽  
Malonyl Coa ◽  
Glucose Fatty Acid Cycle

Malonyl-CoA is an inhibitor of carnitine palmitoyltransferase I, the enzyme that controls the oxidation of fatty acids by regulating their transfer into the mitochondria. Despite this, knowledge of how malonyl-CoA levels are regulated in skeletal muscle, the major site of fatty acid oxidation, is limited. Two- to fivefold increases in malonyl-CoA occur in rat soleus muscles incubated with glucose or glucose plus insulin for 20 min [Saha, A. K., T. G. Kurowski, and N. B. Ruderman. Am. J. Physiol. 269 (Endocrinol. Metab. 32): E283-E289, 1995]. In addition, as reported here, acetoacetate in the presence of glucose increases malonyl-CoA levels in the incubated soleus. The increases in malonyl-CoA in all of these situations correlated closely with increases in the concentration of citrate (r2 = 0.64) and to an even greater extent the sum of citrate plus malate (r2 = 0.90), an antiporter for citrate efflux from the mitochondria. Where measured, no increase in the activity of acetyl-CoA carboxylase (ACC) was found. Inhibition of ATP citrate lyase with hydroxycitrate markedly diminished the increases in malonyl-CoA in these muscles, indicating that citrate was the major substrate for the malonyl-CoA precursor, cytosolic acetyl-CoA. Studies with enzyme purified by immunoprecipitation indicated that the observed increases in citrate could have also allosterically activated ACC. The results suggest that in the presence of glucose, insulin and acetoacetate acutely increase malonyl-CoA levels in the incubated soleus by increasing the cytosolic concentration of citrate. This novel mechanism could complement the glucose-fatty acid cycle in determining how muscle chooses its fuels. It could also provide a means by which glucose acutely modulates signal transduction in muscle and other cells (e.g., the pancreatic beta-cell) in which its metabolism is determined by substrate availability.

Acetyl-CoA provision and the acetyl group deficit at the onset of contraction in ischemic canine skeletal muscle

2005 ◽  
Vol 288 (2) ◽  
pp. E327-E334 ◽  
Author(s):  
Paul A. Roberts ◽  
Susan J. G. Loxham ◽  
Simon M. Poucher ◽  
Dumitru Constantin-Teodosiu ◽  
Paul L. Greenhaff
Keyword(s):  
Skeletal Muscle ◽  
Energy Production ◽  
Pyruvate Dehydrogenase Complex ◽  
Tca Cycle ◽  
Treated Group ◽  
Acetyl Coa ◽  
Tension Development ◽  
The Tca Cycle ◽  
Work Transition ◽  
Acetyl Group

We examined the effects of increasing acetylcarnitine and acetyl-CoA availability at rest, independent of pyruvate dehydrogenase complex (PDC) activation, on energy production and tension development during the rest-to-work transition in canine skeletal muscle. We aimed to elucidate whether the lag in PDC-derived acetyl-CoA delivery toward the TCA cycle at the onset of exercise can be overcome by increasing acetyl group availability independently of PDC activation or is intimately dependent on PDC-derived acetyl-CoA. Gracilis muscle pretreated with saline or sodium acetate (360 mg/kg body mass) (both n = 6) was sampled repeatedly during 5 min of ischemic contraction. Acetate increased acetylcarnitine and acetyl-CoA availability (both P < 0.01) above control at rest and throughout contraction ( P < 0.05), independently of differences in resting PDC activation between treatments. Acetate reduced oxygen-independent ATP resynthesis ∼40% ( P < 0.05) during the first minute of contraction. No difference in oxygen-independent ATP resynthesis existed between treatments from 1 to 3 min of contraction; however, energy production via this route increased ∼25% ( P < 0.05) above control in the acetate-treated group during the final 2 min of contraction. Tension development was ∼20% greater after 5-min contraction after acetate treatment than in control ( P < 0.05). In conclusion, at the immediate onset of contraction, when PDC was largely inactive, increasing cellular acetyl group availability overcame inertia in mitochondrial ATP regeneration. However, after the first minute, when PDC was near maximally activated in both groups, it appears that PDC-derived acetyl-CoA, rather than increased cellular acetyl group availability per se, dictated mitochondrial ATP resynthesis.

Glacial Acetic Acid Catalyzed Synthesis, Physicochemical and Biological Evaluation of Benzodiazepines as Potent CNS Agents

2019 ◽  
Vol 19 (2) ◽  
pp. 146-151
Author(s):  
Vipin Kumar ◽  
Shweta Verma ◽  
Sushil Kumar
Keyword(s):  
Skeletal Muscle ◽  
Muscle Relaxant ◽  
Treated Group ◽  
Biological Evaluation ◽  
Log P ◽  
Control Group ◽  
Skeletal Muscle Relaxant ◽  
Benzodiazepine Derivatives ◽  
Chloro Group ◽  
Muscle Relaxant Activity

Background: Approach for green chemistry for chemical synthesis is found to be very efficient as it makes the reaction more easily, less tedious, maximize desired products and minimize by-products. Materials & Methods: Utilizing this approach 1, 5-benzodiazepines and its derivatives have been synthesized and evaluated for skeletal muscle and antianxiety activity. 1, 5-benzodiazepine derivatives have attracted great attention due to its diversity of pharmacological activities and its application in heterocyclic synthesis and medicines. The target compounds were synthesized by first reacting o-phenylenediamine with acetophenone to yield 1, 5-benzodiazepines. In the next step the NH of 1, 5-benzodiazepines were chloroacetylated and then the chloro group was substituted with different anilines. The structures were confirmed on the basis of their TLC, IR, 1H NMR and CHN elemental studies. The physicochemical parameters were determined for BBB penetration through online software. Results: The Log P values of the compounds tested showed that compounds have the potential to be CNS active. The compounds were evaluated for the skeletal muscle relaxant activity and antianxiety activity. It was investigated that 1, 5-benzodiazepines derivatives possess significant differences between control group and treated group. Conclusion: Among these derivatives, the compound bearing chloro group possesses the highest skeletal muscle relaxant and antianxiety activity.

Effects ofS-nitroso-N-acetylcysteine on contractile function of reperfused skeletal muscle

1998 ◽  
Vol 274 (3) ◽  
pp. R822-R829 ◽  
Author(s):  
Long-En Chen ◽  
Anthony V. Seaber ◽  
Rima M. Nasser ◽  
Jonathan S. Stamler ◽  
James R. Urbaniak
Keyword(s):  
Skeletal Muscle ◽  
Reperfusion Injury ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Protective Role ◽  
Control Group ◽  
Group Vi ◽  
No Donor ◽  
Early Reperfusion ◽  
Reconstructive Operations

The ultimate goal of replantation and microsurgical reconstructive operations is to regain or improve impaired function of the tissue. However, the data related to the influence of NO on tissue function are limited. This study evaluated the effects of the NO donor S-nitroso- N-acetylcysteine (SNAC) on contractile function of skeletal muscle during reperfusion. Forty-nine rats were divided into six groups. The extensor digitorum longus (EDL) muscles in groups I and II were not subjected to ischemia-reperfusion but were treated with a low (100 nmol/min) or high (1 μmol/min) dose of SNAC. In groups III- V, the EDL underwent 3 h of ischemia and 3 h of reperfusion and was also treated with low (100 nmol/min) or high doses (1 or 5 μmol/min) of SNAC. Group VI was a phosphate-buffered saline (PBS)-treated control group. Twenty additional animals were used to document systemic effects of SNAC and PBS only. SNAC or PBS was infused for 6.5 h, beginning 30 min before ischemia and continuing throughout the duration of reperfusion. Contractile testing compared the maximal twitch force, isometric tetanic contractile forces, fatigue, and fatigue half time of the experimental EDL and the contralateral nontreated EDL. The findings indicate that 1) SNAC does not influence contractile function of EDL muscle not subjected to ischemia-reperfusion, 2) SNAC significantly protects the contractile function of ischemic skeletal muscle against reperfusion injury in the early reperfusion period, and 3) the protective role of SNAC is critically dosage dependent; protection is lost at higher doses. The conclusion from this study is that supplementation with exogenous NO exerts a protective effect on the tissue against reperfusion injury.

scholarly journals PSIX-29 JAK2-STAT3 Pathway Mediated Satellite Cell Apoptosis to Govern Skeletal Muscle Growth with Lysine

2020 ◽  
Vol 98 (Supplement_4) ◽  
pp. 334-334
Author(s):  
Zhi-wen Song ◽  
Cheng-long Jin ◽  
Mao Ye ◽  
Chun-qi Gao ◽  
Hui-chao Yan ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Growth ◽  
Longissimus Dorsi ◽  
Control Group ◽  
Stat3 Pathway ◽  
Skeletal Muscle Growth ◽  
Longissimus Dorsi Muscle ◽  
Dorsi Muscle ◽  
Pathway Inhibition ◽  
Induced Apoptosis

Abstract Apoptosis is programmed cell death that can be stimulated by external stress or nutrition restrictions. Lysine (Lys) is an essential amino acid for pig growth, and the relationship between Lys deficiency caused apoptosis and inhibition of skeletal muscle growth remains unknown. The objective of this study was to investigate whether apoptosis could be regulated by Lys supplementation and the potential mechanism. In current work, 30 male Duroc × Landrace × Large weaned piglets were divided randomly into 3 groups: control group (Lys 1.30%), Lys deficiency group (Lys 0.86%), and Lys rescue group (Lys 0.86%, 0-14d; 1.30%,15–28 d). The experiment lasted for 28 days, and on the morning of 29 d, piglets were slaughtered to collect samples. Isobaric tag for relative and absolute quantification (iTRAQ) proteomics analysis of the longissimus dorsi muscle showed that Janus family tyrosine kinase (JAK)-signal transducer and activator of transcription (STAT) pathway was involved in Lys deficiency-induced apoptosis and inhibited skeletal muscle growth. Meanwhile, western blotting results of the longissimus dorsi muscle demonstrated that Lys deficiency caused apoptosis (P &lt; 0.05) with the JAK2-STAT3 pathway inhibition (P &lt; 0.05). Interestingly, apoptosis was suppressed (P &lt; 0.05), and the JAK2-STAT3 pathway was reactivated (P &lt; 0.05) after Lys re-supplementation in longissimus dorsi muscle. In addition, results of satellite cells (SCs) isolated from the longissimus dorsi muscle of 5-day-old Landrace piglets showed that Lys deficiency-induced apoptosis (P &lt; 0.05) was mediated by the JAK2-STAT3 pathway inhibition (P &lt; 0.05). Moreover, the JAK2-STAT3 pathway was reactivated (P &lt; 0.05) by Lys re-supplementation and suppressed apoptosis in SCs (P &lt; 0.05), and this effect was blocked (P &lt; 0.05) after SCs treated with AG-490 (a specific inhibitor of JAK2). Collectively, Lys inhibited apoptosis in SCs to govern skeletal muscle growth via the JAK2-STAT3 pathway.

scholarly journals Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex

1998 ◽  
Vol 329 (1) ◽  
pp. 191-196 ◽  
Author(s):  
Melissa M. BOWKER-KINLEY ◽  
I. Wilhelmina DAVIS ◽  
Pengfei WU ◽  
A. Robert HARRIS ◽  
M. Kirill POPOV
Keyword(s):  
Tissue Distribution ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Pyruvate Dehydrogenase Kinase ◽  
Synthetic Analogue ◽  
Complex Activity ◽  
Acetyl Coa ◽  
Tissue Specific ◽  
Specific Regulation ◽  
Dehydrogenase Complex

Tissue distribution and kinetic parameters for the four isoenzymes of pyruvate dehydrogenase kinase (PDK1, PDK2, PDK3 and PDK4) identified thus far in mammals were analysed. It appeared that expression of these isoenzymes occurs in a tissue-specific manner. The mRNA for isoenzyme PDK1 was found almost exclusively in rat heart. The mRNA for PDK3 was most abundantly expressed in rat testis. The message for PDK2 was present in all tissues tested but the level was low in spleen and lung. The mRNA for PDK4 was predominantly expressed in skeletal muscle and heart. The specific activities of the isoenzymes varied 25-fold, from 50 nmol/min per mg for PDK2 to 1250 nmol/min per mg for PDK3. Apparent Ki values of the isoenzymes for the synthetic analogue of pyruvate, dichloroacetate, varied 40-fold, from 0.2 mM for PDK2 to 8 mM for PDK3. The isoenzymes were also different with respect to their ability to respond to NADH and NADH plus acetyl-CoA. NADH alone stimulated the activities of PDK1 and PDK2 by 20 and 30% respectively. NADH plus acetyl-CoA activated these isoenzymes nearly 200 and 300%. Under comparable conditions, isoenzyme PDK3 was almost completely unresponsive to NADH, and NADH plus acetyl-CoA caused inhibition rather than activation. Isoenzyme PDK4 was activated almost 2-fold by NADH, but NADH plus acetyl-CoA did not activate above the level seen with NADH alone. These results provide the first evidence that the unique tissue distribution and kinetic characteristics of the isoenzymes of PDK are among the major factors responsible for tissue-specific regulation of the pyruvate dehydrogenase complex activity.

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