Adenine nucleotide degradation in human skeletal muscle during prolonged exercise

Broberg, S.; Sahlin, Kent

doi:10.1152/jappl.1989.67.1.116

Cited by 121 publications

(81 citation statements)

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“…These findings are consistent with studies on exhausted skeletal muscles (45). Although undetected in the present study, purine metabolism generates ammonia, which is a known muscle fatigue factor (46). Therefore, the depletion of energy sources and accumulation of inhibitors of muscle contraction (e.g., ammonia) are factors for muscle fatigue (failure of muscle contraction).…”

Section: Biochemical Insight Into the Development Of Exhaustion And Csupporting

confidence: 93%

Astrocytic glycogen-derived lactate fuels the brain during exhaustive exercise to maintain endurance capacity

Matsui

Omuro

Liu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

125

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Brain glycogen stored in astrocytes provides lactate as an energy source to neurons through monocarboxylate transporters (MCTs) to maintain neuronal functions such as hippocampus-regulated memory formation. Although prolonged exhaustive exercise decreases brain glycogen, the role of this decrease and lactate transport in the exercising brain remains less clear. Because muscle glycogen fuels exercising muscles, we hypothesized that astrocytic glycogen plays an energetic role in the prolonged-exercising brain to maintain endurance capacity through lactate transport. To test this hypothesis, we used a rat model of exhaustive exercise and capillary electrophoresismass spectrometry-based metabolomics to observe comprehensive energetics of the brain (cortex and hippocampus) and muscle (plantaris). At exhaustion, muscle glycogen was depleted but brain glycogen was only decreased. The levels of MCT2, which takes up lactate in neurons, increased in the brain, as did muscle MCTs. Metabolomics revealed that brain, but not muscle, ATP was maintained with lactate and other glycogenolytic/glycolytic sources. Intracerebroventricular injection of the glycogen phosphorylase inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol did not affect peripheral glycemic conditions but suppressed brain lactate production and decreased hippocampal ATP levels at exhaustion. An MCT2 inhibitor, α-cyano-4-hydroxycinnamate, triggered a similar response that resulted in lower endurance capacity. These findings provide direct evidence for the energetic role of astrocytic glycogen-derived lactate in the exhaustive-exercising brain, implicating the significance of brain glycogen level in endurance capacity. Glycogen-maintained ATP in the brain is a possible defense mechanism for neurons in the exhausted brain.brain glycogen | lactate transport | ATP | endurance capacity | metabolomics G lucose derived from blood is the primary energy source for generating ATP in the brain, but an important energy reserve is brain glycogen synthesized from glucose in astrocytes (1). Astrocytic glycogen is broken down through glycogenolysis/glycolysis to produce lactate as a neuronal energy substrate transported by monocarboxylate transporters (MCTs) (2). Indeed, brain glycogen decreases during memory tasks (3) and in some physiologically exhaustive conditions such as sleep deprivation (4) and hypoglycemia (5). The genetic/pharmacologic inhibitions of glycogenolysis and/or lactate transport impair neuronal survival under severe hypoglycemia, as well as axon transmission and hippocampus-related memory formation (6-8). Therefore, astrocytic glycogen-derived lactate is a critical energy source for meeting brain energy demands for neuronal functions and/or survival.Although less than for exercising muscles, physical exercise activates brain neurons and increases brain energy demand (9). Blood glucose and lactate contribute to brain energetics during moderate or intense exercise (10, 11). Muscle glycogen is an important energy for maintaining muscle contraction during endurance ex...

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Section: Biochemical Insight Into the Development Of Exhaustion And Csupporting

confidence: 93%

Astrocytic glycogen-derived lactate fuels the brain during exhaustive exercise to maintain endurance capacity

Matsui

Omuro

Liu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

125

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“…No reductions in either of these highenergy phosphagen compounds were evident in freeze-dried tissue, either in the mixed homogenate or in specific fibre types. In the case of ATP, several previous studies have either demonstrated no change (Norman et al 1987) or a reduction in ATP (Broberg & Sahlin, 1989;Green et al 1989) in freeze-dried tissue of mixed fibre types during two-legged cycling at intensities comparable or moderately higher than employed in this study. In the one study published examining ATP levels in type I and type II fibres following 60 min of exercise at 70% V02 max, no change in ATP concentration was evident in either fibre type (Norman et al 1987).…”

Section: Discussioncontrasting

confidence: 53%

“…An additional and important objective of this study was to examine the timedependent change in energy status in type I and type II fibres because of the assertion that glycogen depletion in contracting muscle cells is accompanied by a reduction in the rate of ATP resynthesis (Broberg & Sahlin, 1989). Consequently, reductions in ATP concentration were expected, particularly late in exercise and in type I fibres where a large percentage of the fibres had low or very low concentrations of glycogen.…”

Section: Discussionmentioning

confidence: 99%

Energy metabolism in human slow and fast twitch fibres during prolonged cycle exercise.

Ball-Burnett

Green

Houston

1991

The Journal of Physiology

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SUMMARY1. The effects of prolonged exercise on energy metabolism in type I and type II muscle fibres in the vastus lateralis muscle were investigated in six male subjects (20-0 + 0.5 years, mean + S.E.M.) who performed one-legged cycling at 61 % of maximum 02 consumption (V02 max; determined with one leg) until fatigue or for a maximnum of 2 h.2. Analysis of pools of freeze-dried fibres obtained by needle biopsy and separated into specific types by the myofibrillar ATPase histochemical procedure indicated higher (P < 0 05) lactate concentrations in type II fibres compared to type I fibres at 15 min (43 9+9 7 and 512 +9 8 mmol (kg dry wt)-') and at 60 min (18-2+4-7 and 25-9 + 65 mmol (kg dry wt)-1). No differences existed in lactate concentration between fibre types for pre-exercise (10-0+ 1-6 and 13-3+2 8 mmol (kg dry wt)-') or post-exercise.3. Glycogen degradation was most pronounced in type I fibres. By the end of exercise, glycogen concentration was 82 4+45 mmol glucosyl units (kg dry wt)-' in type I fibres and 175 + 62 mmol glucosyl units (kg dry wt)-1 in type II fibres.4. No significant changes in ATP and creatine phosphate (CrP) were found in either fibre type with exercise.5. It is concluded that, at least for lactate and glycogen, fibre-specific differences are evident in prolonged submaximal exercise. The cause of the difference probably relates both to the unique energy metabolic characteristics of each fibre type and to the manner in which they are utilized during the exercise.

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“…All of these scenarios are associated with a significant increase in muscle adenine nucleotide loss during exercise (21)(22)(23)25,26) and consequently the development of muscle fatigue (17,18,(25)(26)(27)(28). Based on the emerging likelihood that GPis will be used clinically in the treatment of type 2 diabetes, we felt it important to address the effects of glycogen phosphorylase administration on skeletal muscle energy metabolism and function.…”

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confidence: 99%

Glycogen Phosphorylase Inhibition in Type 2 Diabetes Therapy

2005

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Inhibition of hepatic glycogen phosphorylase is a promising treatment strategy for attenuating hyperglycemia in type 2 diabetes. Crystallographic studies indicate, however, that selectivity between glycogen phosphorylase in skeletal muscle and liver is unlikely to be achieved. Furthermore, glycogen phosphorylase activity is critical for normal skeletal muscle function, and thus fatigue may represent a major development hurdle for this therapeutic strategy. We have carried out the first systematic evaluation of this important issue. The rat gastrocnemius-plantaris-soleus (GPS) muscle was isolated and perfused with a red cell suspension, containing 3 mol/l glycogen phosphorylase inhibitor (GPi) or vehicle (control). After 60 min, the GPS muscle was snap-frozen (rest, n ‫؍‬ 11 per group) or underwent 20 s of maximal contraction (n ‫؍‬ 8, control; n ‫؍‬ 9, GPi) or 10 min of submaximal contraction (n ‫؍‬ 10 per group). GPi pretreatment reduced the activation of the glycogen phosphorylase a form by 16% at rest, 25% after 20 s, and 44% after 10 min of contraction compared with the corresponding control. AMP-mediated glycogen phosphorylase activation was impaired only at 10 min (by 21%). GPi transiently reduced muscle lactate production during contraction, but other than this, muscle energy metabolism and function remained unaffected at both contraction intensities. These data indicate that glycogen phosphorylase inhibition aimed at attenuating hyperglycaemia is unlikely to negatively impact muscle metabolic and functional capacity. Diabetes 54: 2453-2459, 2005 G lycogen phosphorylase catalyzes the breakdown of glycogen to glucose-1-phosphate in liver and tissues with high and fluctuating energy demands. Glycogen phosphorylase exists in two interconvertible forms (a and b); the proportion that exists in each form is regulated by phosphorylation. The less active b form is transformed by phosphorylation to the more active a form. In skeletal muscle, the transformation from b to a is regulated by changes in intracellular concentrations of AMP, inosine monophosphate (IMP), and inorganic phosphate and by glycogen phosphorylase kinase activation, all of which increase during contraction. Glycogen phosphorylase kinase also exists in two forms, glycogen phosphorylase kinase a and glycogen phosphorylase kinase b. Glycogen phosphorylase kinase b activity is increased in the presence of elevated intracellular calcium (Ca ϩ2 ) and cAMP, mediated by contraction (1-4) and adrenaline (5-7), respectively, which then phosphorylates and activates glycogen phosphorylase kinase a. Phosphorylated glycogen phosphorylase kinase a then phosphorylates and transforms glycogen phosphorylase b to its more active a form. On cessation of contraction, calcium is sequestered back into the sarcoplasmic reticulum, and the elevated concentrations of ADP, AMP, and inorganic phosphate are used to regenerate muscle ATP and phosphocreatine (PCr) stores. Glycogen phosphorylase a form is subsequently dephosphorylated by the action of protein phosphatases, wher...

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Adenine nucleotide degradation in human skeletal muscle during prolonged exercise

Cited by 121 publications

References 0 publications

Astrocytic glycogen-derived lactate fuels the brain during exhaustive exercise to maintain endurance capacity

Astrocytic glycogen-derived lactate fuels the brain during exhaustive exercise to maintain endurance capacity

Energy metabolism in human slow and fast twitch fibres during prolonged cycle exercise.

Glycogen Phosphorylase Inhibition in Type 2 Diabetes Therapy

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