Skeletal Muscle Glycogen Research Articles

Exercise endurance capacity is markedly reduced due to impaired energy homeostasis during prolonged fasting in FABP4/5 deficient mice

BackgroundSkeletal muscle prefers carbohydrate use to fatty acid (FA) use as exercise intensity increases. In contrast, skeletal muscle minimizes glucose use and relies more on FA during fasting. In mice deficient for FABP4 and FABP5 (double knockout (DKO) mice), FA utilization by red skeletal muscle and the heart is markedly reduced by the impairment of trans-endothelial FA transport, with an increase in glucose use to compensate for reduced FA uptake even during fasting. We attempted to determine whether prolonged fasting affects exercise performance in DKO mice, where constant glucose utilization occurs.ResultsA single bout of treadmill exercise was performed in the fed and fasted states. The initial speed was 10 m/min, and gradually increased by 5 m/min every 5 min up to 30 m/min until the mice stopped running. Running distance was significantly reduced by DKO genotype and prior fasting, leading to the shortest distance in fasted DKO mice. Levels of glycogen in skeletal muscle and the liver were nearly depleted in both WT and DKO mice during prolonged fasting prior to exercise. Levels of TG in skeletal muscle were not reduced by exercise in fasted DKO mice, suggesting that intramuscular TG was not utilized during exercise. Hypoglycaemia was accelerated in fasted DKO mice, and this acceleration could be due to constant glucose utilization by red skeletal muscle and the heart where FA uptake is diminished due to defective trans-endothelial FA transport. Taken together, energy supply from serum and storage in skeletal muscle were very low in fasted DKO mice, which could lead to a significant reduction in exercise performance.ConclusionsFABP4/5 have crucial roles in nutrient homeostasis during prolonged fasting for maintaining exercise endurance capacity.

Effects of Centella asiatica on skeletal muscle structure and key enzymes of glucose and glycogen metabolism in type 2 diabetic rats

BackgroundDysregulation of glucose and glycogen metabolism are crucial mechanisms implicated in type 2 diabetes mellitus (T2DM). Centella asiatica (L.) Urban (Apiaceae) has been utilized as a traditional medicine in Africa and Asia for centuries and is commercially available as a dietary supplement. AimWe explored for the first time, the possible efficacy of Centella asiatica (CA) extract in ameliorating T2DM-induced changes in key enzymes involved in glucose and glycogen metabolism in the rat skeletal muscle. MethodsDiabetic rats were orally treated with vehicle, CA (500 and 1000 mg/kg) or metformin (300 mg/kg) daily for 14 days. Skeletal muscle activities of hexokinase (HK), phosphofructokinase (PFK) and fructose 1,6-bisphosphatase (FBPase) were determined by spectrophotometric assays while those of glycogen synthase (GS) and glycogen phosphorylase (GP) were assayed radio-chemically. Histological examination of skeletal muscle was also performed. ResultsRats with induced T2DM had reduced activities of HK (25%), PFK (88%), and GS (38%) when compared to non-diabetic rats. Treatment of diabetic rats with CA500 increased the activities of PFK (7-fold), and FBPase (23%). Further, treatment of diabetic rats with CA1000 also increased the activities of GS (27%) and GP (50%) with little change in these parameters for diabetic rats treated with CA500. These effects probably led to the reduced blood glucose level and elevated skeletal muscle glycogen content observed in CA-treated rats relative to diabetic controls. Furthermore, CA treated rats had reduced the morphological damage of skeletal muscle fibres compared to the non-treated diabetic control rats. ConclusionOur findings strongly suggest that the anti-diabetic effects of CA in part target muscle glucose and glycogen metabolism and hence supporting its folkloric medical use as an anti-diabetic remedy.

The effects of maltodextrin and protein supplementation on serum metabolites in exercising competitive weight-pulling dogs

Post-exercise carbohydrate repletion of skeletal muscle glycogen utilising maltodextrin, with or without highly digestible protein, can improve performance in humans which has been extrapolated to dogs. There is limited metabolic evidence regarding substrate utilisation during exercise with and without supplementation other than serum hormone status and serum amino acid responses. The objectives of this study were 2-fold; (1) to examine the metabolomic changes associated with a weight-pulling exercise; and (2) to examine the effects of maltodextrin/protein supplementation on serum metabolomics during recovery. Serum was collected from 12 dogs (6 control and 6 treatment) at different time points (pre-exercise, 0 min post-exercise, 30 min post, 3 h post) and liquid chromatography-mass spectrometry (LC-MS) was performed identifying 242 metabolites. A two-way analysis of variance for time and treatment with false discovery rate correction was performed using MetaboAnalyst 3.0. There were 9 metabolites found to be significantly increased or decreased immediately after exercise from baseline representing primarily citric acid cycle metabolites. Treatment differences at 30 min post-exercise showed increases in 8 metabolites including amino acids and carbohydrate intermediates with supplementation. Thirty-seven metabolites were significantly different at 3 h post-exercise, with most metabolites being related to amino acid increases, as well as decreases in fatty acid metabolites with supplementation. Definite alterations in metabolites suggesting that post-exercise supplementation with maltodextrin and protein supports glucose metabolism and alters fatty acid metabolism or clearance during recovery from a weight-pulling exercise.

Glikogen Otot Rangka Ayam Broiler (Gallus gallus) setelah Pemberian Teh Kombucha dalam Air Minum

Kombucha tea beverage obtained by fermenting sweetened green tea for 12 days with Acetobacter xylinum and Saccharomyces which produce various kinds of organic acids, vitamins, and acts as a probiotic. The role of kombucha tea as a growth promoter is to that improve the metabolic process in the digestion of broiler chickens, so that nutrients can and fulfilled optimally for growth and development. The aim of this research was to analyze the sceletal muscle glycogen glycogen (Gallus gallus) after treat with kombucha tea in drinking water. Kombucha tea used is the result of fermentation of green tea for 12 days. This research used DOC chickens (Day Old Chicken) as much as 20 randomly divided into 4 treatments with concentration ie 0%, 10%, 20%, and 40% kombucha tea in drinking water for 32 days. The variables measured were skeletal muscle glycogen levels, body weight, feed consumption and drink consumption. The data obtained were analyzed using ANOVA followed by Duncan Test with 95% confidence level using SPSS 17.0 software. The results of this study showed that kombucha tea on skeletal muscle glycogen and feed consumption showed no significant difference, while on body weight and drink consumption showed significantly different results. Based on the results of the study, it can be concluded that giving kombucha tea in drinking water to a concentration of 40% has not been able to affect the skeletal muscle glycogen in broiler chickens. Key words: Kombucha tea, broiler chicken, glycogen skeletal muscle

Influence of coadministration of metformin and methanolic stem extract of Anisopus mannii N.E.Br. (Apocynaceae) on glucose homeostasis and lipid profile in streptozotocin/nicotinamide-induced diabetic rats

Background: Although the antihyperglycemic activity of stem extracts of Anisopus mannii (AM; an antidiabetic ethnomedicinal plant utilized in Northwestern Nigeria) has been reported, the effects of coadministration of the extracts with glibenclamide, a commonly used antihyperglycemic agent, are not known. Aims and Objectives: The objectives were to determine the effect of simultaneous administration of AM methanolic stem extract with glibenclamide using streptozotocin/nicotinamide-induced diabetic rats. Materials and Methods: After permission from the departmental ethics committee, male Wistar rats were assigned to five groups: Vehicle-treated normal control; vehicle-treated diabetic control; diabetic rats treated with either glibenclamide (0.6 mg/kg) or methanolic stem extract of AM (200 mg/kg), and singly or in combination. Fasting blood glucose (FBG) and oral glucose tolerance test (OGTT) were performed at days 14 and 28 of treatment, while lipid profile and the contents of hepatic and skeletal muscle glycogen were determined at the end of the study (day 29). Results: When combined, the AM extract significantly reduced (P < 0.05) the effect of glibenclamide in lowering the total area under the OGTT curve as well as the FBG level and in increasing the contents of hepatic and skeletal muscle glycogen as well as the blood level of high-density lipoprotein cholesterol. The two treatments also significantly reduced each other’s effect in lowering triglycerides, low-density lipoprotein, and total cholesterol. Conclusion: The methanolic stem extract of AM (200 mg/kg) combined with glibenclamide (0.6 mg/kg) reduced each other’s beneficial effects on glucose homeostasis and lipid profile in streptozotocin/nicotinamide-induced diabetic rats.

Glycogen metabolism and glycogen storage disorders.

Glucose is the main energy fuel for the human brain. Maintenance of glucose homeostasis is therefore, crucial to meet cellular energy demands in both - normal physiological states and during stress or increased demands. Glucose is stored as glycogen primarily in the liver and skeletal muscle with a small amount stored in the brain. Liver glycogen primarily maintains blood glucose levels, while skeletal muscle glycogen is utilized during high-intensity exertion, and brain glycogen is an emergency cerebral energy source. Glycogen and glucose transform into one another through glycogen synthesis and degradation pathways. Thus, enzymatic defects along these pathways are associated with altered glucose metabolism and breakdown leading to hypoglycemia ± hepatomegaly and or liver disease in hepatic forms of glycogen storage disorder (GSD) and skeletal ± cardiac myopathy, depending on the site of the enzyme defects. Overall, defects in glycogen metabolism mainly present as GSDs and are a heterogenous group of inborn errors of carbohydrate metabolism. In this article we review the genetics, epidemiology, clinical and metabolic findings of various types of GSD, and glycolysis defects emphasizing current treatment and implications for future directions.

No evidence of direct association between GLUT4 and glycogen in human skeletal muscle.

Previous studies have demonstrated that exercise increases whole body and skeletal muscle insulin sensitivity that is linked with increased GLUT4 at the plasma membrane following insulin stimulation and associated with muscle glycogen depletion. To assess the potential direct association between muscle glycogen and GLUT4, seven untrained, male subjects exercised for 60 min at ~75% VO2 peak, with muscle samples obtained by percutaneous needle biopsy immediately before and after exercise. Exercise reduced muscle glycogen content by ~43%. An ultracentrifugation protocol resulted in a ~2‐3‐fold enriched glycogen fraction from muscle samples for analysis. Total GLUT4 content was unaltered by exercise and we were unable to detect any GLUT4 in glycogen fractions, either with or without amylase treatment. In skinned muscle fiber segments, there was very little, if any, GLUT4 detected in wash solutions, except following exposure to 1% Triton X‐100. Amylase treatment of single fibers did not increase GLUT4 in the wash solution and there were no differences in GLUT4 content between fibers obtained before or after exercise for any of the wash treatments. Our results indicate no direct association between GLUT4 and glycogen in human skeletal muscle, before or after exercise, and suggest that alterations in GLUT4 translocation associated with exercise‐induced muscle glycogen depletion are mediated via other mechanisms.

Phenotypic Modulation of Skeletal Muscle Fibers in LPIN1-Deficient Lipodystrophic ( fld) Mice.

Lipin-1 ( Lpin1)-deficient lipodystrophic mice have scant and immature adipocytes and develop transient fatty liver early in life. Unlike normal mice, these mice cannot rely on stored triglycerides to generate adenosine triphosphate (ATP) from the β-oxidation of fatty acids during periods of fasting. To compensate, these mice store much higher amounts of glycogen in skeletal muscle and liver than wild-type mice in order to support energy needs during periods of fasting. Our studies demonstrated that there are phenotypic changes in skeletal muscle fibers that reflect an adaptation to this unique metabolic situation. The phenotype of skeletal muscle (soleus, gastrocnemius, plantaris, and extensor digitorum longus [EDL]) from Lpin1-/- was evaluated using various methods including immunohistochemistry for myosin heavy chains (Myh) 1, 2, 2a, 2b, and 2x; enzyme histochemistry for myosin ATPase, cytochrome-c oxidase (COX), and succinyl dehydrogenase (SDH); periodic acid-Schiff; and transmission electron microscopy. Fiber-type changes in the soleus muscle of Lpin1-/- mice were prominent and included decreased Myh1 expression with concomitant increases in Myh2 expression and myosin-ATPase activity; this change was associated with an increase in the presence of Myh1/2a or Myh1/2x hybrid fibers. Alterations in mitochondrial enzyme activity (COX and SDH) were apparent in the myofibers in the soleus, gastrocnemius, plantaris, and EDL muscles. Electron microscopy revealed increases in the subsarcolemmal mitochondrial mass in the muscles of Lpin1-/- mice. These data demonstrate that lipin-1 deficiency results in phenotypic fiber-specific modulation of skeletal muscle necessary for compensatory fuel utilization adaptations in lipodystrophy.

Single Dose Administration of Taheebo Polyphenol Enhances Endurance Capacity in Mice

Endurance capacity is important for maintenance of quality of life as well as performance of endurance athletes. In order to improve endurance, intake of nutritional supplements as well as exercise training is also important. Indeed, polyphenolic extracts from plants are known to improve endurance capacity via increase of fatty acid utilization, mitochondrial biogenesis or inhibition of oxidative stress. Taheebo, the extract obtained from inner bark of Tabebuia avellanedae has been reported to have beneficial effects for treatment of inflammation, oxidative stress and obesity. Here, we investigated the effects and mechanisms of polyphenol fraction of taheebo (taheebo polyphenol; TP) on endurance capacity of mice. Single dose administration of TP significantly increased running time until exhaustion. Acute TP administration increased blood glucose and muscle glycogen levels (p < 0.05) through alteration on expression level of genes involved with glycogen metabolism and gluconeogenesis. Furthermore, TP administration decreased exercise-induced increase of protein carbonyls in skeletal muscle. These results suggest that TP administration improve endurance capacity via up-regulation of skeletal muscle glycogen levels and maintenance of blood glucose by acceleration of gluconeogenesis as well as inhibition of exercise-induced oxidative stress. Single administration of TP also increased phosphorylation of AMP-activated protein kinase (AMPK) and gene expression level of sirtuin 1 (SIRT1) but did not change the marker of mitochondrial biogenesis.

Effect of Chronic Hyperglycemia on Glucose Metabolism in Subjects With Normal Glucose Tolerance.

Chronic hyperglycemia causes insulin resistance, but the inheritability of glucotoxicity and the underlying mechanisms are unclear. We examined the effect of 3 days of hyperglycemia on glucose disposal, enzyme activities, insulin signaling, and protein O-GlcNAcylation in skeletal muscle of individuals without (FH−) or with (FH+) family history of type 2 diabetes. Twenty-five subjects with normal glucose tolerance received a [3-3H]glucose euglycemic insulin clamp, indirect calorimetry, and vastus-lateralis biopsies before and after 3 days of saline (n = 5) or glucose (n = 10 FH− and 10 FH+) infusion to raise plasma glucose by ∼45 mg/dL. At baseline, FH+ had lower insulin-stimulated glucose oxidation and total glucose disposal (TGD) but similar nonoxidative glucose disposal and basal endogenous glucose production (bEGP) compared with FH−. After 3 days of glucose infusion, bEGP and glucose oxidation were markedly increased, whereas nonoxidative glucose disposal and TGD were lower versus baseline, with no differences between FH− and FH+ subjects. Hyperglycemia doubled skeletal muscle glycogen content and impaired activation of glycogen synthase (GS), pyruvate dehydrogenase, and Akt, but protein O-GlcNAcylation was unchanged. Insulin resistance develops to a similar extent in FH− and FH+ subjects after chronic hyperglycemia, without increased protein O-GlcNAcylation. Decreased nonoxidative glucose disposal due to impaired GS activation appears to be the primary deficit in skeletal muscle glucotoxicity.

NEW THERAPEUTIC APPROACHES AND THEIR READOUT: O.20Results from ATB200-02: first-in-human, open-label, phase 1/2 study of ATB200 co-administered with AT2221 for Pompe disease

Late-onset Pompe disease (LOPD) is caused by impaired lysosomal glycogen clearance due to acid alpha-glucosidase (GAA) deficiency. Accumulation of glycogen in skeletal muscle and diaphragm leads to loss of muscle and respiratory function. Recombinant human GAA enzyme replacement therapy (rhGAA ERT; alglucosidase alfa) is standard treatment for LOPD. ATB200-02 (NCT02675465) is a first-in-human, open-label, Phase 1/2 trial to evaluate ATB200, a next-generation rhGAA ERT, co-administered with AT2221, an oral pharmacological chaperone, in adults with LOPD. Twenty patients (pts) were enrolled: ERT-switch ambulatory (Cohort 1, n=11), ERT-switch nonambulatory (Cohort 2, n=4), and ERT-naive ambulatory (Cohort 3, n=5). Mean±SD 6-minute walk test increased for ambulatory ERT-switch (Month [Mo] 6 [n=10], +23.9±52.2; Mo 9 [n=10], +24.5±40.8; Mo 12 [n=8], +57.4±34.4 m) and ERT-naive pts (Mo 6 [n=5], +41.8±29.4; Mo 9 [n=5], +63.5±23.1; Mo 12 [n=2], +86.8±11.1 m). Other motor function tests were generally consistent with these results. Increases were observed in upper extremity strength in nonambulatory ERT-switch pts at Mo 6 and 9. Forced vital capacity (% predicted) increased in ERT-naive pts (Mo 6 [n=5], +4.2; Mo 9 [n=5], +6.2; Mo 12 [n=2], +6.0) and was generally stable in ambulatory ERT-switch pts (Mo 6 [n=9], -1.3; Mo 9 [n=9], -1.7; Mo 12 [n=7], -3.1). All cohorts demonstrated improvements in the Fatigue Severity Scale. ATB200/AT2221 was associated with reductions in creatine kinase and urine hexose tetrasaccharide. The most common treatment-emergent adverse events were upper and lower abdominal pain (n=8), diarrhea (n=8), and nasopharyngitis (n=6). Three events of infusion-associated reactions occurred in 550+ infusions. Data from this interim analysis show a clinical benefit of ATB200/AT2221 in ERT-naive pts and in pts who have been on ERT for ∼5 years. ATB200/AT2221 has the potential to be a significant treatment alternative for patients with Pompe disease.

METABOLIC MYOPATHIES II: P.357Expression analysis of glycogenin-1 and glycogenin-2 in patients with glycogen storage disease XV

Glycogen storage disease type XV (GSD15) is caused by mutations in the GYG1 gene, which encodes glycogenin-1, a primer for biosynthesis of glycogen. Patients with GYG1-mutations are characterized by either absent or non-functional glycogenin-1, and storage of glycogen or polyglucosan in skeletal muscle. There is also storage in the heart in some patients with cardiomyopathy. Despite the fact that glycogenin-1 is considered to be required for glycogen synthesis, glycogen is present in muscles of glycogenin-1 deficient patients. A role of glycogenin-2 as an alternative primer for glycogen synthesis has been suggested. While glycogenin-1 is ubiquitously expressed, glycogenin-2 is mainly expressed in the liver. To investigate the importance of glycogenin-1 and the role of glycogenin-2, we performed western blot analyses, mass spectrometry, and immunohistochemistry on tissue specimens from GYG1-mutated patients and controls. Expression of both glycogenin-1 and glycogenin-2 was present in control liver specimens, but only glycogenin-1 was identified in heart and skeletal muscle of controls. In patients with truncating GYG1-mutations neither glycogenin-1 nor glycogenin-2 was expressed in skeletal muscle. However, glycogenin-1 but not glycogenin-2 was identified in the heart of patients with cardiomyopathy due to GYG1 missense mutations. Immunohistochemistry demonstrated that glycogenin-1 was localised to the storage of glycogen or polyglucosan in cardiomyocytes. In conclusion, glycogen can be synthesised in the absence of glycogenin-1 and up-regulation of glycogenin-2 does not compensate for glycogenin-1 deficiency. Absence of glycogenin-1 leads to accumulation of glycogen and polyglucosan in skeletal muscle fibers. Expression of glycogenin-1 with missense mutations is deleterious to the heart and leads to storage of glycogenin-1 and abnormal glycogen.

METABOLIC MYOPATHIES II: P.352A novel recombinant human acid alpha-glucosidase, ATB200, co-administered with a pharmacological chaperone, leads to greater substrate reduction and improvement in Pompe disease-relevant markers compared to alglucosidase alfa in Gaa KO mice

Pompe disease is an inherited lysosomal storage disorder caused by a deficiency in acid alpha-glucosidase (GAA) activity, and is characterized by progressive accumulation of lysosomal glycogen in cardiac and skeletal muscles. Enzyme replacement therapy using recombinant human GAA (rhGAA), alglucosidase alfa, is currently the only approved treatment for Pompe disease. However, alglucosidase alfa may have limitations in delivery to skeletal muscles due to sub-optimal levels of mannose-6-phosphate (M6P), a carbohydrate that binds cation-independent M6P receptors at the cell surface to mediate enzyme internalization and lysosomal delivery. We have developed a novel rhGAA (designated ATB200) with a significantly higher M6P content compared to alglucosidase alfa; ATB200 is further stabilized by the small molecule pharmacological chaperone, AT2221 (miglustat). In this study, we compared the effects of ATB200, orally co-administered with AT2221 (ATB200/AT2221; co-administration), to those of alglucosidase alfa in Gaa knockout (KO) mice. Repeat administration of ATB200/AT2221 resulted in substantially greater enzyme levels in lysosomes and significant glycogen reduction in key skeletal muscles. Importantly, extensive histological analysis of Gaa KO mouse muscle showed that ATB200/AT2221 is more effective compared to alglucosidase alfa in correcting overall cellular dysfunction in the endocytic-lysosomal-autophagic pathways, including lysosomal proliferation and autophagic buildup, the two known hallmarks of Pompe disease. Notably, these positive changes correlated well with improvements in muscle strength and muscle fiber size. Collectively, these data indicate that ATB200, stabilized by the pharmacological chaperone AT2221, offers potential advantages over the standard of care, and warrants further investigation as a next-generation treatment in patients with Pompe disease.

Glycogen metabolism and glycogen storage disorders

Glucose is the main energy fuel for the human brain. Maintenance of glucose homeostasis is therefore, crucial to meet cellular energy demands in both - normal physiological states and during stress or increased demands. Glucose is stored as glycogen primarily in the liver and skeletal muscle with a small amount stored in the brain. Liver glycogen primarily maintains blood glucose levels, while skeletal muscle glycogen is utilized during high-intensity exertion, and brain glycogen is an emergency cerebral energy source. Glycogen and glucose transform into one another through glycogen synthesis and degradation pathways. Thus, enzymatic defects along these pathways are associated with altered glucose metabolism and breakdown leading to hypoglycemia ± hepatomegaly and or liver disease in hepatic forms of glycogen storage disorder (GSD) and skeletal ± cardiac myopathy, depending on the site of the enzyme defects. Overall, defects in glycogen metabolism mainly present as GSDs and are a heterogenous group of inborn errors of carbohydrate metabolism. In this article we review the genetics, epidemiology, clinical and metabolic findings of various types of GSD, and glycolysis defects emphasizing current treatment and implications for future directions.

Hepatic and skeletal muscle glycogen content in rats treated with metformin and submitted to acute exercise by swimming

O objetivo deste estudo foi avaliar o comportamento das reservas glicogênicas de ratos, submetidos a uma condição de exercício agudo (50 minutos de natação na intensidade leve), após o tratamento com metformina. Quarenta ratos Wistar (180-200g) adultos foram divididos em quatro grupos (tratados ou não por quinze dias) e assim representados: Controle; Exercício agudo por natação (realizaram uma sessão de natação, sendo 50 minutos na intensidade leve); Tratado com metformina (receberam o fármaco metformina na dosagem de 1,4 mg/ml, durante o período experimental; Tratados com metformina e submetidos a condição exercício agudo por natação (receberam o fármaco metformina na dosagem de 1,4 mg/ml e realizaram uma sessão de natação, sendo 50 minutos na intensidade leve). O exercício agudo diminuiu as reservas glicogênicas, já os animais tratados com metformina, apresentaram um aumento em suas reservas glicogênicas musculares e hepáticas em relação ao grupo que realizou o exercício sem suplementação (p0,05). O tratamento com metformina promoveu melhora nas condições energéticas e menor resposta ao estresse, sugerindo ser uma importante ferramenta farmacológica para a potencialização da performance.

Skeletal Muscle Glycogen Content at Rest and During Endurance Exercise in Humans: A Meta-Analysis.

Skeletal muscle glycogen is an important energy source for muscle contraction and a key regulator of metabolic responses to exercise. Manipulation of muscle glycogen is therefore a strategy to improve performance in competitions and potentially adaptation to training. However, assessing muscle glycogen in the field is impractical, and there are no normative values for glycogen concentration at rest and during exercise. The objective of this study was to meta-analyse the effects of fitness, acute dietary carbohydrate (CHO) availability and other factors on muscle glycogen concentration at rest and during exercise of different durations and intensities. PubMed was used to search for original articles in English published up until February 2018. Search terms included muscle glycogen and exercise, filtered for humans. The analysis incorporated 181 studies of continuous or intermittent cycling and running by healthy participants, with muscle glycogen at rest and during exercise determined by biochemical analysis of biopsies. Resting muscle glycogen was determined with a meta-regression mixed model that included fixed effects for fitness status [linear, as maximal oxygen uptake ([Formula: see text]O2max) in mL·kg-1·min-1] and CHO availability (three levels: high, ≥ 6g·kg-1 of CHO per day for ≥ 3days or ≥ 7g·kg-1 CHO per day for ≥ 2days; low, glycogen depletion and low-CHO diet; and normal, neither high nor low, or not specified in study). Muscle glycogen during exercise was determined with a meta-regression mixed model that included fixed effects for fitness status, resting glycogen [linear, in mmol·kg-1 of dry mass (DM)], exercise duration (five levels, with means of 5, 23, 53 and 116min, and time to fatigue), and exercise intensity (linear, as percentage of [Formula: see text]O2max); intensity, fitness and resting glycogen were interacted with duration, and there were also fixed effects for exercise modes, CHO ingestion, sex and muscle type. Random effects in both models accounted for between-study variance and within-study repeated measurement. Inferences about differences and changes in glycogen were based on acceptable uncertainty in standardised magnitudes, with thresholds for small, moderate, large and very large of 25, 75, 150 and 250mmol·kg-1 of DM, respectively. The resting glycogen concentration in the vastus lateralis of males with normal CHO availability and [Formula: see text]O2max (mean ± standard deviation, 53 ± 8mL·kg-1·min-1) was 462 ± 132mmol·kg-1. High CHO availability was associated with a moderate increase in resting glycogen (102, ± 47mmol·kg-1; mean ± 90% confidence limits), whereas low availability was associated with a very large decrease (- 253, ± 30mmol·kg-1). An increase in [Formula: see text]O2max of 10mL·kg-1·min-1 had small effects with low and normal CHO availability (29, ± 44 and 67, ± 15mmol·kg-1, respectively) and a moderate effect with high CHO availability (80, ± 40mmol·kg-1). There were small clear increases in females and the gastrocnemius muscle. Clear modifying effects on glycogen utilisation during exercise were as follows: a 30% [Formula: see text]O2max increase in intensity, small (41, ± 20mmol·kg-1) at 5min and moderate (87-134mmol·kg-1) at all other timepoints; an increase in baseline glycogen of 200mmol·kg-1, small at 5-23min (28-59mmol·kg-1), moderate at 116min (104, ± 15mmol·kg-1) and moderate at fatigue (143, ± 33mmol·kg-1); an increase in [Formula: see text]O2max of 10mL·kg-1·min-1, mainly clear trivial effects; exercise mode (intermittent vs. continuous) and CHO ingestion, clear trivial effects. Small decreases in utilisation were observed in females (vs. males: - 30, ± 29mmol·kg-1), gastrocnemius muscle (vs. vastus lateralis: - 31, ± 46mmol·kg-1) and running (vs. cycling: - 70, ± 32mmol·kg-1). Dietary CHO availability and fitness are important factors for resting muscle glycogen. Exercise intensity and baseline muscle glycogen are important factors determining glycogen use during exercise, especially with longer exercise duration. The meta-analysed effects may be useful normative values for prescription of endurance exercise.

Elevated Nicotinamide Phosphoribosyl Transferase in Skeletal Muscle Augments Exercise Performance and Mitochondrial Respiratory Capacity Following Exercise Training.

Mice overexpressing NAMPT in skeletal muscle (NamptTg mice) develop higher exercise endurance and maximal aerobic capacity (VO2max) following voluntary exercise training compared to wild-type (WT) mice. Here, we aimed to investigate the mechanisms underlying by determining skeletal muscle mitochondrial respiratory capacity in NamptTg and WT mice. Body weight and body composition, tissue weight (gastrocnemius, quadriceps, soleus, heart, liver, and epididymal white adipose tissue), skeletal muscle and liver glycogen content, VO2max, skeletal muscle mitochondrial respiratory capacity (measured by high-resolution respirometry), skeletal muscle gene expression (measured by microarray and qPCR), and skeletal muscle protein content (measured by Western blot) were determined following 6 weeks of voluntary exercise training (access to running wheel) in 13-week-old male NamptTg (exercised NamptTg) mice and WT (exercised WT) mice. Daily running distance and running time during the voluntary exercise training protocol were recorded. Daily running distance (p = 0.51) and running time (p = 0.85) were not significantly different between exercised NamptTg mice and exercised WT mice. VO2max was higher in exercised NamptTg mice compared to exercised WT mice (p = 0.02). Body weight (p = 0.92), fat mass (p = 0.49), lean mass (p = 0.91), tissue weight (all p > 0.05), and skeletal muscle (p = 0.72) and liver (p = 0.94) glycogen content were not significantly different between exercised NamptTg mice and exercised WT mice. Complex I oxidative phosphorylation (OXPHOS) respiratory capacity supported by fatty acid substrates (p < 0.01), maximal (complex I+II) OXPHOS respiratory capacity supported by glycolytic (p = 0.02) and fatty acid (p < 0.01) substrates, and maximal uncoupled respiratory capacity supported by fatty acid substrates (p < 0.01) was higher in exercised NamptTg mice compared to exercised WT mice. Transcriptomic analyses revealed differential expression for genes involved in oxidative metabolism in exercised NamptTg mice compared to exercised WT mice, specifically, enrichment for the gene set related to the SIRT3-mediated signaling pathway. SIRT3 protein content correlated with NAMPT protein content (r = 0.61, p = 0.04). In conclusion, NamptTg mice develop higher exercise capacity following voluntary exercise training compared to WT mice, which is paralleled by higher mitochondrial respiratory capacity in skeletal muscle. The changes in SIRT3 targets suggest that these effects are due to remodeling of mitochondrial function.

Distinct Clinical and Genetic Findings in Iranian Patients With Glycogen Storage Disease Type 3.

Glycogen storage disease type 3 (GSD-III) is a rare inherited metabolic disorder caused by glycogen debranching enzyme deficiency. Various pathogenic mutations of the AGL gene lead to abnormal accumulation of glycogen in liver, skeletal, and cardiac muscles. Here, we report distinct clinical and genetic data of Iranian patients with GSD-III. Clinical and laboratory data of 5 patients with GSD-III were recorded. Genetic investigation was performed to identify the causative mutations. Three patients had typical liver involvement in childhood and one was diagnosed 2 years after liver transplantation for cirrhosis of unknown etiology. Four patients had vacuolar myopathy with glycogen excess in muscle biopsy. All patients had novel homozygous mutations of the AGL gene namely c.378T>A, c.3295T>C, c.3777G>A, c.2002-2A>G, and c.1183C>T. This is the first comprehensive report of patients with GSD-III in Iran with 2 uncommon clinical presentations and 5 novel mutations in the AGL gene.

Endospanin-2 enhances skeletal muscle energy metabolism and running endurance capacity.

Metabolic stresses such as dietary energy restriction or physical activity exert beneficial metabolic effects. In the liver, endospanin-1 and endospanin-2 cooperatively modulate calorie restriction-mediated (CR-mediated) liver adaptations by controlling growth hormone sensitivity. Since we found CR to induce endospanin protein expression in skeletal muscle, we investigated their role in this tissue. In vivo and in vitro endospanin-2 triggers ERK phosphorylation in skeletal muscle through an autophagy-dependent pathway. Furthermore, endospanin-2, but not endospanin-1, overexpression decreases muscle mitochondrial ROS production, induces fast-to-slow fiber-type switch, increases skeletal muscle glycogen content, and improves glucose homeostasis, ultimately promoting running endurance capacity. In line, endospanin-2-/- mice display higher lipid peroxidation levels, increased mitochondrial ROS production under mitochondrial stress, decreased ERK phosphorylation, and reduced endurance capacity. In conclusion, our results identify endospanin-2 as a potentially novel player in skeletal muscle metabolism, plasticity, and function.

Postexercise Fructose–Maltodextrin Ingestion Enhances Subsequent Endurance Capacity

Restoring skeletal muscle and hepatic glycogen content during short-term (<6 h) recovery from prolonged exercise is pertinent for athletes seeking to maximize performance in repeated exercise bouts. Previous research suggests that coingestion of fructose-glucose carbohydrate sources augments hepatic and has equivalent effects on skeletal muscle glycogen storage during short-term recovery from prolonged exercise compared with isocaloric glucose ingestion. The aim of the present investigation was to determine whether this has a discernible effect on subsequent exercise capacity. Eight trained endurance runners and triathletes performed two experimental trials in a single-blind, randomized, and counterbalanced crossover design. Trials involved treadmill running to exhaustion at 70% V˙O2max, a 4-h recovery with 90 g·h of glucose-maltodextrin (GLU + MAL) or fructose-maltodextrin (FRU + MAL) ingestion (1:1.5 ratio), and a second bout of treadmill running to exhaustion at 70% V˙O2max. Exercise capacity in bout 2 was significantly greater with FRU + MAL (81.4 ± 22.3 vs 61.4 ± 9.6 min, P = 0.02), a large magnitude effect (effect size = 1.84 ± 1.12, 32.4% ± 19.9%). Total carbohydrate oxidation rates were not significantly different during bout 1 or 2 between trials, although total carbohydrate oxidized in bout 2 was significantly greater with FRU + MAL (223 ± 66 vs 157 ± 26 g, P = 0.02). Ingested carbohydrate oxidation rates were greater during bout 2 with FRU + MAL (P = 0.001). Plasma glucose and nonesterified fatty acid concentrations were not significantly different between trials. Plasma lactate concentrations were significantly greater during recovery before bout 2 with FRU + MAL (P = 0.001). Self-reported nausea and stomach fullness during bout 2 were marginally in favor of FRU + MAL. Short-term recovery of endurance capacity was significantly enhanced with FRU + MAL versus GLU + MAL ingestion during recovery.