Energy substrate metabolism in skeletal muscle and liver when consuming diets of different energy levels: comparison between Tibetan and Small-tailed Han sheep

The human body requires energy to function. Adenosine triphosphate (ATP) is the cellular currency for energy-requiring processes including mechanical work (i.e., exercise). ATP used by the cells is ultimately derived from the catabolism of energy substrate molecules—carbohydrates, fat, and protein. In prolonged moderate to high-intensity exercise, there is a delicate interplay between carbohydrate and fat metabolism, and this bioenergetic process is tightly regulated by numerous physiological, nutritional, and environmental factors such as exercise intensity and duration, body mass and feeding state. Carbohydrate metabolism is of critical importance during prolonged endurance-type exercise, reflecting the physiological need to regulate glucose homeostasis, assuring optimal glycogen storage, proper muscle fuelling, and delaying the onset of fatigue. Fat metabolism represents a sustainable source of energy to meet energy demands and preserve the ‘limited’ carbohydrate stores. Coordinated neural, hormonal and circulatory events occur during prolonged endurance-type exercise, facilitating the delivery of fatty acids from adipose tissue to the working muscle for oxidation. However, with increasing exercise intensity, fat oxidation declines and is unable to supply ATP at the rate of the exercise demand. Protein is considered a subsidiary source of energy supporting carbohydrates and fat metabolism, contributing to approximately 10% of total ATP turnover during prolonged endurance-type exercise. In this review we present an overview of substrate metabolism during prolonged endurance-type exercise and the regulatory mechanisms involved in ATP turnover to meet the energetic demands of exercise.

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Neuromuscular Electrical Stimulation Improves Energy Substrate Metabolism and Survival in Mice With Acute Endotoxic Shock

Shock ◽

10.1097/shk.0000000000001354 ◽

2020 ◽

Vol 53 (2) ◽

pp. 236-241

Author(s):

Takayuki Irahara ◽

Norio Sato ◽

Kosuke Otake ◽

Satoru Murata ◽

Kazuo Inoue ◽

...

Keyword(s):

Electrical Stimulation ◽

Endotoxic Shock ◽

Neuromuscular Electrical Stimulation ◽

Energy Substrate ◽

Substrate Metabolism

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The KATP channel Kir6.2 subunit content is higher in glycolytic than oxidative skeletal muscle fibers

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00663.2010 ◽

2011 ◽

Vol 301 (4) ◽

pp. R916-R925 ◽

Cited By ~ 18

Author(s):

Krystyna Banas ◽

Charlene Clow ◽

Bernard J. Jasmin ◽

Jean-Marc Renaud

Keyword(s):

Skeletal Muscle ◽

Cross Sections ◽

Fiber Type ◽

Energy Levels ◽

Muscle Fibers ◽

Metabolic Stress ◽

Oxidative Capacity ◽

Fiber Types ◽

Fiber Damage ◽

The Individual

It has long been suggested that in skeletal muscle, the ATP-sensitive K+ channel (KATP) channel is important in protecting energy levels and that abolishing its activity causes fiber damage and severely impairs function. The responses to a lack of KATP channel activity vary between muscles and fibers, with the severity of the impairment being the highest in the most glycolytic muscle fibers. Furthermore, glycolytic muscle fibers are also expected to face metabolic stress more often than oxidative ones. The objective of this study was to determine whether the t-tubular KATP channel content differs between muscles and fiber types. KATP channel content was estimated using a semiquantitative immunofluorescence approach by staining cross sections from soleus, extensor digitorum longus (EDL), and flexor digitorum brevis (FDB) muscles with anti-Kir6.2 antibody. Fiber types were determined using serial cross sections stained with specific antimyosin I, IIA, IIB, and IIX antibodies. Changes in Kir6.2 content were compared with changes in CaV1.1 content, as this Ca2+ channel is responsible for triggering Ca2+ release from sarcoplasmic reticulum. The Kir6.2 content was the lowest in the oxidative soleus and the highest in the glycolytic EDL and FDB. At the individual fiber level, the Kir6.2 content within a muscle was in the order of type IIB > IIX > IIA ≥ I. Interestingly, the Kir6.2 content for a given fiber type was significantly different between soleus, EDL, and FDB, and highest in FDB. Correlations of relative fluorescence intensities from the Kir6.2 and CaV1.1 antibodies were significant for all three muscles. However, the variability in content between the three muscles or individual fibers was much greater for Kir6.2 than for CaV1.1. It is suggested that the t-tubular KATP channel content increases as the glycolytic capacity increases and as the oxidative capacity decreases and that the expression of KATP channels may be linked to how often muscles/fibers face metabolic stress.

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Skeletal muscle uncoupling-induced longevity in mice is linked to increased substrate metabolism and induction of the endogenous antioxidant defense system

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00518.2012 ◽

2013 ◽

Vol 304 (5) ◽

pp. E495-E506 ◽

Cited By ~ 26

Author(s):

S. Keipert ◽

M. Ost ◽

A. Chadt ◽

A. Voigt ◽

V. Ayala ◽

...

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Antioxidant Defense ◽

Antioxidant Defense System ◽

Mapk Signaling ◽

Redox Signaling ◽

Defense System ◽

High Fat ◽

Substrate Metabolism ◽

Endogenous Antioxidant

Ectopic expression of uncoupling protein 1 (UCP1) in skeletal muscle (SM) mitochondria increases lifespan considerably in high-fat diet-fed UCP1 Tg mice compared with wild types (WT). To clarify the underlying mechanisms, we investigated substrate metabolism as well as oxidative stress damage and antioxidant defense in SM of low-fat- and high-fat-fed mice. Tg mice showed an increased protein expression of phosphorylated AMP-activated protein kinase, markers of lipid turnover (p-ACC, FAT/CD36), and an increased SM ex vivo fatty acid oxidation. Surprisingly, UCP1 Tg mice showed elevated lipid peroxidative protein modifications with no changes in glycoxidation or direct protein oxidation. This was paralleled by an induction of catalase and superoxide dismutase activity, an increased redox signaling (MAPK signaling pathway), and increased expression of stress-protective heat shock protein 25. We conclude that increased skeletal muscle mitochondrial uncoupling in vivo does not reduce the oxidative stress status in the muscle cell. Moreover, it increases lipid metabolism and reactive lipid-derived carbonyls. This stress induction in turn increases the endogenous antioxidant defense system and redox signaling. Altogether, our data argue for an adaptive role of reactive species as essential signaling molecules for health and longevity.

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Dietary amino acids: effect of depletion and recovery on synthesis in vitro in rat skeletal muscle and liver

British Journal Of Nutrition ◽

10.1079/bjn19740009 ◽

1974 ◽

Vol 31 (1) ◽

pp. 67-76 ◽

Cited By ~ 26

Author(s):

P. T. Omstedt ◽

Alexandra Von Der Decken

Keyword(s):

Skeletal Muscle ◽

Amino Acid ◽

Energy Levels ◽

Wheat Gluten ◽

Amino Acid Mixture ◽

Acid Mixture ◽

Amino Acid Mixtures ◽

Wet Weight ◽

Ribosomal Activity

1. Rats were given diets containing 200 g/kg of a complete or incomplete amino acid mixture or of high- or low-quality proteins. After 6 d the amino acid-incorporating activity of ribosomes from skeletal muscle and liver was studied.2. The level of isotope incorporation relative to ribosomal RNA was similar for casein supplemented with methionine and for a complete amino acid mixture with the composition of whole-egg protein. Per wet weight of tissue there was a significant decrease after feeding with the complete amino acid mixture.3. There was a significant decrease in activity after feeding with amino acid mixtures deficient in lysine, methionine or tryptophan. In skeletal muscle, but not in liver, the ribosomal activity was less than that obtained with wheat gluten. Activity per wet weight of both tissues was less than that obtained with wheat gluten.4. Refeeding with methionine for 1 d resulted in complete restoration of ribosomal activity and activity per wet weight in skeletal muscle.5. After lysine deficiency, protein synthesis per unit wet weight of both tissues and ribosomal activity in liver were not restored after 2 d of refeeding. Recovery of ribosomal activity in skeletal muscle was complete after 1 d.6. Rats receiving the 200 g casein/kg diet supplemented with methionine at daily energy levels of 263, 176, 141 and 106 KJ (62.6, 42.1, 33.7 and 25.3 kcal) showed no changes in ribosomal activity, but there was a significant decrease in activity per wet weight when 106 KJ were given.

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Energy substrate metabolism among habitually violent alcoholic offenders having antisocial personality disorder

Psychiatry Research ◽

10.1016/j.psychres.2006.01.013 ◽

2007 ◽

Vol 150 (3) ◽

pp. 287-295 ◽

Cited By ~ 19

Author(s):

Matti Virkkunen ◽

Aila Rissanen ◽

Hannu Naukkarinen ◽

Anja Franssila-Kallunki ◽

Markku Linnoila ◽

...

Keyword(s):

Personality Disorder ◽

Antisocial Personality Disorder ◽

Antisocial Personality ◽

Energy Substrate ◽

Substrate Metabolism

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Deranged energy substrate metabolism in the failing heart

Current Hypertension Reports ◽

10.1007/s11906-006-0024-9 ◽

2006 ◽

Vol 8 (6) ◽

pp. 465-471 ◽

Cited By ~ 8

Author(s):

Qi Tian ◽

Philip M. Barger

Keyword(s):

Energy Substrate ◽

Substrate Metabolism ◽

Failing Heart

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Isoflurane Alters Energy Substrate Metabolism to Preserve Mechanical Function in Isolated Rat Hearts following Prolonged No-Flow Hypothermic Storage

Anesthesiology ◽

10.1097/00000542-200302000-00018 ◽

2003 ◽

Vol 98 (2) ◽

pp. 379-386 ◽

Cited By ~ 8

Author(s):

Barry A. Finegan ◽

Manoj Gandhi ◽

Matthew R. Cohen ◽

Donald Legatt ◽

Alexander S. Clanachan

Keyword(s):

Enhanced Recovery ◽

Metabolic Effects ◽

Mechanical Function ◽

Cardioplegic Arrest ◽

Channel Activation ◽

Energy Substrate ◽

Myocardial Glucose Metabolism ◽

Substrate Metabolism ◽

Rat Hearts

Background Isoflurane enhances mechanical function in hearts subject to normothermic global or regional ischemia. The authors examined the effectiveness of isoflurane in preserving mechanical function in hearts subjected to cardioplegic arrest and prolonged hypothermic no-flow storage. The role of isoflurane in altering myocardial glucose metabolism during storage and reperfusion during these conditions and the contribution of adenosine triphosphate-sensitive potassium (K(atp)) channel activation in mediating the functional and metabolic effects of isoflurane preconditioning was determined. Methods Isolated working rat hearts were subjected to cardioplegic arrest with St. Thomas' II solution, hypothermic no-flow storage for 8 h, and subsequent aerobic reperfusion. The consequences of isoflurane treatment were assessed during the following conditions: (1) isoflurane exposure before and during storage; (2) brief isoflurane exposure during early nonworking poststorage reperfusion; and (3) isoflurane preconditioning before storage. The selective mitochondrial and sarcolemmal K(atp) channel antagonists, 5-hydroxydecanoate and HMR 1098, respectively, were used to assess the role of K(atp) channel activation on glycogen consumption during storage in isoflurane-preconditioned hearts. Results Isoflurane enhanced recovery of mechanical function if present before and during storage. Isoflurane preconditioning was also protective. Isoflurane reduced glycogen consumption during storage under the aforementioned circumstances. Storage of isoflurane-preconditioned hearts in the presence of 5-hydroxydecanoate prevented the reduction in glycogen consumption during storage and abolished the beneficial effect of isoflurane preconditioning on recovery of mechanical function. Conclusions Isoflurane provides additive protection of hearts subject to cardioplegic arrest and prolonged hypothermic no-flow storage and favorably alters energy substrate metabolism by modulating glycolysis during ischemia. The effects of isoflurane preconditioning on glycolysis during hypothermic no-flow storage appears to be associated with activation of mitochondrial K(atp) channels.

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Comprehensive metabolic modeling of multiple 13C-isotopomer data sets to study metabolism in perfused working hearts

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00428.2016 ◽

2016 ◽

Vol 311 (4) ◽

pp. H881-H891 ◽

Cited By ~ 12

Author(s):

Scott B. Crown ◽

Joanne K. Kelleher ◽

Rosanne Rouf ◽

Deborah M. Muoio ◽

Maciek R. Antoniewicz

Keyword(s):

Network Model ◽

Metabolic Flux ◽

Parameter Determination ◽

Algebraic Equations ◽

Acetyl Coa ◽

Energy Substrate ◽

Substrate Metabolism ◽

Metabolic Fluxes ◽

Heart Perfusion ◽

Tracer Experiments

In many forms of cardiomyopathy, alterations in energy substrate metabolism play a key role in disease pathogenesis. Stable isotope tracing in rodent heart perfusion systems can be used to determine cardiac metabolic fluxes, namely those relative fluxes that contribute to pyruvate, the acetyl-CoA pool, and pyruvate anaplerosis, which are critical to cardiac homeostasis. Methods have previously been developed to interrogate these relative fluxes using isotopomer enrichments of measured metabolites and algebraic equations to determine a predefined metabolic flux model. However, this approach is exquisitely sensitive to measurement error, thus precluding accurate relative flux parameter determination. In this study, we applied a novel mathematical approach to determine relative cardiac metabolic fluxes using 13C-metabolic flux analysis (13C-MFA) aided by multiple tracer experiments and integrated data analysis. Using 13C-MFA, we validated a metabolic network model to explain myocardial energy substrate metabolism. Four different 13C-labeled substrates were queried (i.e., glucose, lactate, pyruvate, and oleate) based on a previously published study. We integrated the analysis of the complete set of isotopomer data gathered from these mouse heart perfusion experiments into a single comprehensive network model that delineates substrate contributions to both pyruvate and acetyl-CoA pools at a greater resolution than that offered by traditional methods using algebraic equations. To our knowledge, this is the first rigorous application of 13C-MFA to interrogate data from multiple tracer experiments in the perfused heart. We anticipate that this approach can be used widely to study energy substrate metabolism in this and other similar biological systems.

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Effects of adenosine, exercise, and moderate acute hypoxia on energy substrate utilization of human skeletal muscle

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00245.2011 ◽

2012 ◽

Vol 302 (3) ◽

pp. R385-R390 ◽

Cited By ~ 19

Author(s):

Ilkka Heinonen ◽

Jukka Kemppainen ◽

Kimmo Kaskinoro ◽

Juha E. Peltonen ◽

Hannu T. Sipilä ◽

...

Keyword(s):

Skeletal Muscle ◽

Glucose Uptake ◽

Human Skeletal Muscle ◽

Acute Hypoxia ◽

Knee Extension ◽

Substrate Utilization ◽

Energy Substrate ◽

Skeletal Muscle Glucose Uptake ◽

Knee Extension Exercise

Glucose metabolism increases in hypoxia and can be influenced by endogenous adenosine, but the role of adenosine for regulating glucose metabolism at rest or during exercise in hypoxia has not been elucidated in humans. We studied the effects of exogenous adenosine on human skeletal muscle glucose uptake and other blood energy substrates [free fatty acid (FFA) and lactate] by infusing adenosine into the femoral artery in nine healthy young men. The role of endogenous adenosine was studied by intra-arterial adenosine receptor inhibition (aminophylline) during dynamic one-leg knee extension exercise in normoxia and acute hypoxia corresponding to ∼3,400 m of altitude. Extraction and release of energy substrates were studied by arterial-to-venous (A-V) blood samples, and total uptake or release was determined by the product of A-V differences and muscle nutritive perfusion measured by positron emission tomography. The results showed that glucose uptake increased from a baseline value of 0.2 ± 0.2 to 2.0 ± 2.2 μmol·100 g−1·min−1 during adenosine infusion ( P < 0.05) at rest. Although acute hypoxia enhanced arterial FFA levels, it did not affect muscle substrate utilization at rest. During exercise, glucose uptake was higher (195%) during acute hypoxia compared with normoxia ( P = 0.058), and aminophylline had no effect on energy substrate utilization during exercise, despite that arterial FFA levels were increased. In conclusion, exogenous adenosine at rest and acute moderate hypoxia during low-intensity knee-extension exercise increases skeletal muscle glucose uptake, but the increase in hypoxia appears not to be mediated by adenosine.

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