Skeletal Muscle Glycogen Content Research Articles

Effect of Caralluma tuberculata on regulation of carbohydrate metabolizing genes in alloxan-induced rats

Ethnopharmacological relevanceCaralluma tuberculata (C. tuberculata) has traditionally been used in Pakistan and other parts of the world as a folk treatment for diabetes mellitus. A few studies indicated its antihyperglycemic effect, however, the mystery remained unfolded as how did it modify the pathophysiological condition. Aim of studyHence, this study aimed to explore underlying mechanism(s) for its hypoglycemic activity at biochemical and molecular levels. Materials and methodsMethanol extract (ME) of C. tuberculata as well as its hexane (HF) and aqueous (AF) fractions were explored for their effect on total glycogen in liver and skeletal muscle of alloxan-induced rats by spectroscopy. Moreover, the expression of genes related to hepatic carbohydrate metabolizing enzymes was quantified. At molecular level, mRNA expression of glucose transporter 2 (GLUT-2), glycogen synthase (GS), glucokinase (GK), hexokinase 1 (HK-1), pyruvate kinase (PK), glucose 6 phosphate dehydrogenase (G-6-PDH), pyruvate carboxylase (PC), phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6 phosphatase (G-6-Pase) was determined by using quantitative real time polymerase chain reaction (qRT-PCR) after administration of ME (350 mg), HF(3 mg), AF (10 mg) and metformin (500 mg). The doses were administered twice daily according to per kg of body weight. ResultsA significant reduction in hepatic and skeletal muscle glycogen content was exhibited. The data of qRT-PCR revealed that gene's expression of GLUT-2 was significantly decreased after treatment with ME and HF, whilst it was unaltered by AF, however, a significant decrease was observed in genes corresponding to GS, GK and HK-1 after treatment with ME. Similarly, there was a significant decrease in expression of genes corresponding to GS, GK and HK-1 following treatment with HF. Surprisingly, post-treatment with AF didn't modify the gene's expression of GS and GK, whilst it caused a profound decrease in expression of HK-1 gene. Contrarily, the expression of gene related to PK was significantly up-regulated post-administration with ME, HF and AF. The expression levels of G-6-PDH, however, remained unaltered after treatment with the experimental extract and fractions of the plant. In addition, HF and AF did not cause any modification in PEPCK, whereas ME caused a significant down-regulation of the gene. Treatment with all the extract and fractions of the plant caused a substantial decrease in the gene's expression of PC, while there was a significant increase in the expression of gene related to G-6-Pase. ConclusionThe three experimental extract and fractions caused a substantial decrease in glycogen content in liver and skeletal muscle tissues. The analysis by qRT-PCR showed that glucose transport via GLUT-2 was profoundly declined by ME and HF. The expression of genes related to various metabolic pathways involved in metabolism of carbohydrate in hepatocytes revealed explicitly that the ME, HF and AF decreased the phenomena of glycogenesis and gluconeogenesis. Contrarily, all the extract and fractions of the plant activated glycogenolysis and glycolysis but did not modify the pentose phosphate shunt pathway.

Skeletal muscle of females and males with constitutional thinness: a low intramuscular lipid content and oxidative profile.

Constitutional thinness (CT) is a nonpathological state of underweight. The current study aimed to explore skeletal muscle energy storage in individuals with CT and to further characterize muscle phenotype at baseline and in response to overfeeding. Thirty subjects with CT (15 females, 15 males) and 31 normal-weight control subjects (16 females, 15 males) participated in the study. Histological and enzymological analyses were performed on muscle biopsy specimens before and after overfeeding. In the skeletal muscle of CT participants compared with controls, we observed a lower content of intramuscular triglycerides for type I (-17%, p < 0.01) and type IIA (-14%, p < 0.05) muscle fibers, a lower glycogen content for type I (-6%, p < 0.01) and type IIA (-5%, p < 0.05) muscle fibers, a specific fiber-type distribution, a marked muscle hypotrophy (-20%, p < 0.001), a low capillary-to-fiber ratio (-19%, p < 0.001), and low citrate synthase activity (-18%, p < 0.05). In response to overfeeding, CT participants increased their intramuscular triglycerides content in type I (+10%, p < 0.01) and type IIA (+9%, p < 0.01) muscle fibers. CT individuals seem to present an unusual muscle phenotype and different adaptations to overfeeding compared with normal-weight individuals, suggesting a specific energy metabolism and muscle adaptations. ClinicalTrials.gov registration no. NCT02004821. Novelty Low intramuscular triglycerides and glycogen content in skeletal muscle of constitutionally thin individuals. Low oxidative capacity, low capillary supply, and fiber hypotrophy in skeletal muscle of constitutionally thin individuals. Increase in intramuscular triglycerides in constitutional thinness in response to overfeeding.

Comment on: "Changes in Skeletal Muscle Glycogen Content in Professional Soccer Players before and after a Match by a NonInvasive MuscleSound® Technology. A Cross Sectional Pilot Study Nutrients 2020, 12(4), 971".

San-Millán and colleagues [...].

Reply to Comment on: "Changes in Skeletal Muscle Glycogen Content in Professional Soccer Players before and after a Match by a Non-Invasive MuscleSound® Technology. A Cross Sectional Pilot Study Nutrients 2020, 12(4), 971".

In our paper published in this journal, we present a pilot study application of a novel way to "indirectly assess" skeletal muscle glycogen based on the methodology that we developed though high-frequency skeletal muscle ultrasound [...].

Antidiabetic and anti-inflammatory effects of two Fabaceae extracts against streptozotocin induced diabetic impairment in male rats

The present study aimed to investigate the antidiabetic and anti-inflammatory effects of Trifolium alexandrinum (TA) and Trifolium Pretense (TP) against streptozotocin induced diabetic impairment in male rats. Forty adult Wistar albino male rats were divided into four groups: Group 1, Control; Group 2, streptozotocin (STZ); Group 3, STZ + TA –treated group and Group 4, STZ + TP–treated group. TA and TP showed a significant reduction in the blood glucose, glycosylated hemoglobin (Hb A1C) levels and elevation in insulin and C-peptide. They restored the glycogen content of liver and skeletal muscle, also showed improvements in the activities of α-amylase, carbohydrate metabolic enzymes, lipase and lipid profile. Treatment with TA and TP extracts resulted in an improvement of the oxidative parameters and enhancement in the antioxidant enzymes in the pancreas and liver. While, pancreatic TNF-α, IL-1β, IL-6, NO, iNos and caspase-3 levels were significantly reduced with the treatment of TA and TP extracts. Administration of TA and TP extracts to diabetic rats revealed elevation in the GLUT4 levels of the skeletal muscle and pancreas. They caused up regulation in pancreatic GLUT2 gene expression. TA and TP extracts showed signs of regeneration of β-cells and improvement in the pancreatic tissue. It could be concluded that TA and TP extracts possess antioxidant and hypoglycemic potential resulting in reduction of the elevated oxidative stress and pro-inflammatory cytokines.

MondoA Is Required for Normal Myogenesis and Regulation of the Skeletal Muscle Glycogen Content in Mice

BackgroundSkeletal muscle is the largest tissue in the human body, and it plays a major role in exerting force and maintaining metabolism homeostasis. The role of muscle transcription factors in the regulation of metabolism is not fully understood. MondoA is a glucose-sensing transcription factor that is highly expressed in skeletal muscle. Previous studies suggest that MondoA can influence systemic metabolism homeostasis. However, the function of MondoA in the skeletal muscle remains unclear.MethodsWe generated muscle-specific MondoA knockout (MAKO) mice and analyzed the skeletal muscle morphology and glycogen content. Along with skeletal muscle from MAKO mice, C2C12 myocytes transfected with small interfering RNA against MondoA were also used to investigate the role and potential mechanism of MondoA in the development and glycogen metabolism of skeletal muscle.ResultsMAKO caused muscle fiber atrophy, reduced the proportion of type II fibers compared to type I fibers, and increased the muscle glycogen level. MondoA knockdown inhibited myoblast proliferation, migration, and differentiation by inhibiting the phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K)/Akt pathway. Further mechanistic experiments revealed that the increased muscle glycogen in MAKO mice was caused by thioredoxin-interacting protein (TXNIP) downregulation, which led to upregulation of glucose transporter 4 (GLUT4), potentially increasing glucose uptake.ConclusionMondoA appears to mediate mouse myofiber development, and MondoA decreases the muscle glycogen level. The findings indicate the potential function of MondoA in skeletal muscle, linking the glucose-related transcription factor to myogenesis and skeletal myofiber glycogen metabolism.

Effects of post‐exercise lactate administration on glycogen recovery in mouse skeletal muscle

During high‐intensity exercise, glycogen content in skeletal muscle and liver decreases, while lactate accumulates in the circulation. Although sports nutrition guidelines recommend carbohydrate intake for glycogen recovery, the metabolic interaction between ingested carbohydrate and circulating lactate after exercise is unclear. In this study, we examined whether elevated circulating lactate additively enhances post‐exercise glycogen restoration. Eight‐week‐old male ICR mice were allocated to one of four groups as follows: PBS + water (PW) group, lactate + water (LW) group, PBS + glucose (PG) group, and lactate + glucose (LG) group. Animals performed treadmill running (20 m/min, 60 min) following overnight fasting (16 hours). Immediately after the exercise, animals received intraperitoneal injection of PBS or lactate (1 g/kg BW), followed by oral ingestion of water or glucose (2 g/kg BW). At 30, 45, 60 minutes of recovery, blood glucose concentration was higher in the LW group than in the PW group (p&lt;0.05). In contrast, blood glucose level at 15 and 30 minutes of recovery and its iAUC were lower in the LG group than in the PG group (p&lt;0.05). At 60 minutes of recovery, glucose ingestion resulted in higher glycogen content in the soleus, plantaris, and gastrocnemius muscles and the liver of the PG and LG groups compared with the PW group, although plasma insulin level at 15 minutes recovery (p&lt;0.01) and its iAUC (p&lt;0.05) were lower in the LG group than in the PG group. Moreover, lactate injection enhanced glycogen content in the plantaris and gastrocnemius muscles of the LW and LG groups (p&lt;0.05), but not in the soleus muscle and the liver. Our current findings suggest that elevated circulating lactate additively enhances post‐exercise glycogen recovery in glycolytic phenotype muscle.

Indirect Assessment of Skeletal Muscle Glycogen Content in Professional Soccer Players before and after a Match through a Non-Invasive Ultrasound Technology.

Skeletal muscle glycogen (SMG) stores in highly glycolytic activities regulate muscle contraction by controlling calcium release and uptake from sarcoplasmic reticulum, which could affect muscle contraction. Historically, the assessment of SMG was performed through invasive and non-practical muscle biopsies. In this study we have utilized a novel methodology to assess SMG through a non-invasive high-frequency ultrasound. Nine MLS professional soccer players (180.4 ± 5.9 cm; 72.4 ± 9.3 kg; 10.4% ± 0.7% body fat) participated. All followed the nutritional protocol 24 h before the official match as well as performing the same practice program the entire week leading to the match. The SMG decreased from 80 ± 8.6 to 63.9 ± 10.2; p = 0.005 on MuscleSound® score (0–100) representing a 20% ± 10.4% decrease in muscle glycogen after match. Inter-individual differences in both starting glycogen content (65–90) and in percentage decrease in glycogen after the match (between 6.2% and 44.5%). Some players may not start the match with adequate SMG while others’ SMG decreased significantly throughout the game. Adequate pre-match SMG should be achieved during half-time and game-play in order to mitigate the decrease in glycogen. Further and more ample studies are needed before the application of this technology.

Inhibition of glycogenolysis prolongs action potential repriming period and impairs muscle function in rat skeletal muscle.

Muscle glycogen content is associated with muscle function, but the physiological link between the two is poorly understood. This study investigated the effects of inhibiting glycogenolysis, while maintaining high overall energy status, on different aspects of muscle function. We demonstrate here that Na+ ,K+ -ATPase activity depends on glycogenolytically derived ATP regardless of high global ATP, with a decrease in activity leading to reduced force production and accelerated fatigue development. The results support the concept of compartmentalized energy transfer with glycogen metabolism playing a crucial role in intramuscular ATP resynthesis and ion regulation. This study gives specific insights into muscular function and may help towards a better understanding of glycogen storage diseases and muscle fatigue. Skeletal muscle glycogen content is associated with muscle function and fatigability. However, little is known about the physiological link between glycogen content and muscle function. Here we aimed to investigate the importance of glycogenolytically derived ATP per se on muscle force and action potential (AP) repriming period, i.e. the time before a second AP can be produced (indicative of Na+ ,K+ -ATPase activity). Single fibres from rat extensor digitorum longus muscles were isolated and mechanically skinned in order to investigate force production and the AP repriming period while global ATP and PCr concentrations were kept high. The importance of glycogenolytically derived ATP was studied by inhibition of glycogen phosphorylase (1,4-dideoxy-1,4-imino-d-arabinitol (DAB; 2mm) or CP-316,819 (CP; 10µm)) or glycogen removal (amyloglucosidase, 20Uml-1 ). Tetanic force decreased by (mean (SD)) 21(15)% (P<0.001) and 76(28)% (DAB) or 94(6)% (CP, P<0.001) in well-polarized and partially depolarized fibres, respectively. In depolarized fibres, twitch force decreased by 16(10)% and 55(26)% with DAB and CP, respectively, with no effect in well-polarized fibres (84(10)%, P=0.14). There was no effect of glycogen phosphorylase inhibition on repriming period in well-polarized fibres (median (25th, 75th percentile): 5(4,5) vs. 4(4,5)ms, P=0.26), while the repriming period was prolonged from 6(5,7) to 8(7,10)ms (P=0.01) in partially depolarized fibres. In line with this, glycogen removal increased repriming period from 5(5,6) to 6(5,7)ms (P=0.003) in depolarized fibres. Together, these data strongly indicate that blocking glycogenolysis attenuates Na+ ,K+ -ATPase activity, which in turn increases the repriming period and reduces force, demonstrating a functional link between glycogenolytically derived ATP and force production.

Arginine supplementation prevent diabetic mellitus complications on myopathy and visceral organs (liver&pancreas)in experimental model.

The study was designed to investigate the role of arginine on myopathy and some visceral organs like liver and pancreas in diabetic female rats at different period (15,30,45) days post diabetic induction.In this study female rats ( Rattus norvegicus) were used, total number (30) rats were divided into ( non-diabetic and diabetic ) groups, first group with (6) females as control group and diabetic group with (24) rats, this group subdivided into two groups (12) rats on each one, both of them was injected intraperitoneally with single dose about ( 60 mg/kg) B/W from streptozotocin (STZ) with (12) rats at each period (15,30,45) days post (DM) induction one of this two subgroup were given only tap water but the second subgroup (diabetic and treated with arginine)were given L-arginine dissolved in the drinking water as (10mg/L) after (3) days post (STZ) induction.At (15) day post induction the skeletal muscles revealed to atrophied muscle fibers, infarction, irregular, crowded myonuclei, infiltration of inflammatory cells, tapers endings. Moreover at (30) days sever atrophied muscle fibers, myonuclei was detached from their normal location, thick, dark sarcolemma with zigzag shape, while post (45) day sever alterations included filamentous muscle fibers, some completely destructed, wavy fibers, bifurcated and other rounded or circular muscle fibers. The study determined the effect of arginine on diabetic skeletal muscles, post (15) days of induction, the muscle fibers more regular, clear striation, peripheral myonuclei and parallel muscle fibers. post (30) days, normal muscle fibers, number of satellite cells, normal capillaries, regenerated myotubes. At (45) days the muscle fibers with normal diameter, more intense, less inflammation, normal muscle spindles, less congested blood vessels and normal blood walls thickness.Liver sections related to diabetes group showed post (15) days vacuolated hepatocytes with pyknotic nuclei, dilated sinusoids, increased in kupffer cells, mild fatty changes, bile ducts hyperplasia. Post (30) days sever congestion, necrotic foci, hydropic changes, cloudy hepatocytes, swelling with pyknotic nuclei. At (45) days more severity included necrosis, kupffer cells hyperplasia, sever fibrosis, fatty changes. Role of arginine was determined and its effect on liver, after (15) day normal hepatocytes, more regular hepatic plates, mild inflammation, normal periportal area, post (30) days remarkable regeneration, foci of kupffer cells accumulated, proliferation of bile ductules and mild congestion, at (45) days liver structure resemble the control, most hepatocytes was binucleat, arrange in hepatic cords and normal sinusoid.Harmful effect of (DM) on pancreatic tissue which showed after (15) day, shrinkage of Langerhans islets, atrophied pancreatic acini, destruction and necrosis of beta cells, reduced number and size of islets, changes more severity at (30,45) days, revealed to atrophy stroma replaced by fibrous and adipose connective tissue substance, vacuolated and degenerated islets. Whereas pancreas from diabetic rats treated with arginine after (15) day the changes less obvious, more numerous islet of Lankerhanse, regular acini and at (30,45) day normal pancreatic tissue, most islets with normal boundaries, organized pancreatic acini and the protective role on pancreas was noticed.(DM) caused variable changes in glycogen content in both skeletal muscles and liver at each period (15, 30, 45) days. Moreover the results determined the role of arginine on accumulation and stored of glycogen content. The liver from diabetic rats showed the same results and there was mild reduction to moderate and then sever reduction in glycogen content at each period (15,30,45) days respectively whereas restored in glycogen content recorded on rats treated with arginine.The study evaluated changes in cholesterol and Triglycerides( TG) level and the results showed a significant increase at (P<0.05) in their level in all diabetic rats compared to control while significant decrease at (P<0.05) in level of cholesterol and (TG) in rats with (DM) and treated with arginine. Moreover (HDL) showed a significant decrease at (P<0.05) of diabetic rats and there was increase in its concentration in all diabetes rats treated with arginine. Also insulin growth factor like-1 (IGF-1) in all rats related to control and treated group was estimated, the data clarified a significant decrease at (P<0.05) within diabetic group compared to control, while significant increase in rats related to treated group compared to diabetic group.

Hypoglycemic and hypolipidemic effects of a polysaccharide from Fructus Corni in streptozotocin-induced diabetic rats

Type-2 diabetes mellitus and its related complications including dyslipidemia and oxidative stress have been threating the health of a large number of patients all over the world. In this study, FCPC, one polysaccharide fraction separated from the polysaccharides of Chinese medicine Fructus Corni (FCPs), revealed obvious inhibitory effects against α-amylase and α-glucosidase, and marked insulin-sensitizing effect by increasing insulin secretion and promoting pancreatic β cell proliferation. In addition, in streptozotocin (STZ)-induced diabetic rats, the polysaccharide fraction not only significantly restrained the increase of food (p < 0.05) and water (p < 0.01) intake at 800 mg/kg, but also significantly controlled the increase of levels for sugar (p < 0.01), insulin (p < 0.05) and HOMA-IR value (p < 0.05) in blood at 800 mg/kg on 42th day. Meanwhile, the reduced glycogen contents in liver (p < 0.01) and skeletal (p < 0.01) muscle caused by STZ were prominently improved, while the dyslipidemia status and oxidative damage were markedly ameliorated. Therefore, FCPC could be developed to natural medicines and functional foods in the treatment of diabetes and its complications including dyslipidemia status and oxidative stress.

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.

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.

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.

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.

Mitochondria, glycogen, and lipid droplets in skeletal muscle during testosterone treatment and strength training: a randomized, double-blinded, placebo-controlled trial.

Low testosterone levels in aging men are associated with insulin resistance. Mitochondrial dysfunction, changes in glycogen metabolism, and lipid accumulation are linked to insulin resistance in skeletal muscle. In this randomized, double-blinded, placebo-controlled study, we investigated the effects of six-month testosterone replacement therapy (TRT) and strength training (ST) on mitochondrial, glycogen, and lipid droplet (LD) content in skeletal muscle of aging men with subnormal bioavailable testosterone (BioT) levels. Mitochondrial, glycogen, and LD volume fractions in muscle biopsies were estimated by transmission electron microscopy. Insulin sensitivity (insulin-stimulated Rd) and body composition were assessed by euglycemic-hyperinsulinemic clamp and dual X-ray absorptiometry, respectively. TRT significantly increased total testosterone levels, BioT, and lean body mass (LBM) (p<0.05), whereas percent body fat decreased (p<0.05), and insulin sensitivity was unchanged. Baseline mitochondrial volume fraction correlated inversely with percent body fat (ρ=-0.43; p=0.003). Δ-mitochondrial fraction correlated positively with Δ-total testosterone (ρ=0.70; p=0.02), and Δ-glycogen fraction correlated inversely with Δ-LBM (ρ=-0.83; p=0.002) during six-month TRT, but no significant changes were observed in mitochondrial, glycogen, and LD volume fractions during TRT and ST. In conclusion, in this exploratory small-scale study, the beneficial effects of six-month TRT on total testosterone, LBM, and percent body fat were not followed by significant changes in fractions of mitochondria, glycogen, or lipid in skeletal muscle of aging men with lowered testosterone levels. Six-month ST or combined three-month ST+TRT did not change intramyocellular mitochondria, glycogen, and LD fractions compared to placebo. However, further studies with a larger sample size are needed.

Glycogen Enhancement Augments Basal and Leucine‐Stimulated Protein Synthesis in C2C12 Myotubes

Age‐related skeletal muscle wasting is associated with elevated 5′‐AMP‐Activated Protein Kinase (AMPK) activity, which inhibits overload‐induced skeletal muscle protein synthesis (MPS) and growth. Glycogen, an inhibitor of AMPK, is reduced in aged skeletal muscle. We recently found that glycogen enhancement augments 21‐day overload‐induced MPS and growth in aged rat skeletal muscle. Unexpectedly, these findings were largely independent of AMPK and other signaling regulating MPS. However, the effects of glycogen enhancement on the skeletal muscle response to other anabolic stimuli, such as leucine, are largely unknown. Therefore, the purpose of this investigation was to examine the effects of enhanced glycogen on AMPK phosphorylation status and activity, MPS, and MPS‐related signaling in response to leucine in C2C12 myotubes. We hypothesized that glycogen enhancement in myotubes would enhance the anabolic effect of leucine by inhibiting AMPK and increasing anabolic signaling and MPS, and that this effect would be reduced by rapamycin‐induced mechanistic target of rapamycin (mTOR) blockade. Four days after the onset of differentiation, myotubes were transfected (via Lipofectamine 3000) for 48 hrs with a mutant glycogen synthase plasmid (mutant‐GS; designed to enhance skeletal muscle glycogen content) or an empty‐vector plasmid. At six days post‐differentiation, transfected myotubes were serum‐starved for 4 hrs prior to an amino acid starvation for 1 hr. Myotubes were then treated with either a vehicle control (CT), 10 mM leucine (LEU), 100 nM rapamycin (RAP), or leucine/rapamycin co‐treatment (LEU+RAP) for 30 min. All treatment conditions contained 100 μM puromycin for measurement of MPS rate. All values were normalized to the empty‐vector CT condition. As expected, mutant‐GS expression and glycogen content were significantly (p ≤ 0.05) higher in all four mutant‐GS myotube conditions vs. corresponding empty‐vector conditions. Within both the mutant‐GS conditions and the empty‐vector conditions, MPS was stimulated with LEU treatment and suppressed with RAP treatment as expected; however, MPS was significantly (p ≤ 0.05) higher in all four mutant‐GS conditions vs. corresponding empty‐vector conditions. LEU treatment increased the phosphorylation status of mTOR (Ser2448), p70S6K (Thr389), and 4EBP1 (Thr37/46), and this effect was blocked with RAP treatment within both the mutant‐GS myotubes or the empty‐vector myotubes. However, there were no significant (p &gt; 0.05) differences between mutant‐GS or empty‐vector myotubes in this signaling. Additionally, markers of AMPK phosphorylation status (Thr172) and activity (ACC at Ser79) and other MPS signaling intermediates (TSC2 Ser1387 &amp; Thr1462) were not significantly different between mutant‐GS vs. empty‐vector conditions and were unaffected by LEU or RAP treatments. Although the stimulation of MPS by leucine is mTOR‐dependent regardless of glycogen enhancement in myotubes, glycogen enhancement augments MPS independent of changes in AMPK, mTOR, or other MPS‐related signaling markers assessed. Even though the signaling mechanism(s) remain to be identified, these findings along with our recent in vivo data support the translatable potential to enhance human skeletal muscle glycogen content to augment leucine‐stimulated MPS or augment MPS and growth under conditions of chronic overload (such as resistance exercise training).Support or Funding InformationThis research was partially supported by an ACSM Foundation Doctoral Student Research Grant from the American College of Sports Medicine Foundation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.