Changes In Muscle Metabolism Research Articles

Dysregulation of muscle cholesterol transport in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons, with a typical lifespan of 3-5 years. Altered metabolism is a key feature of ALS that strongly influences prognosis, with an increase in whole-body energy expenditure and changes in skeletal muscle metabolism, including greater reliance on fat oxidation. Dyslipidemia has been described in ALS as part of the metabolic dysregulation, but its role in the pathophysiology of the disease remains controversial. Among the lipids, cholesterol is of particular interest as a vital component of cell membranes, playing a key role in signal transduction and mitochondrial function in muscle. The aim of this study was to investigate whether motor dysfunction in ALS might be associated with dysregulation of muscle cholesterol metabolism. We determined cholesterol content and analyzed the expression of key determinants of the cholesterol metabolism pathway in muscle biopsies from thirteen ALS patients and ten asymptomatic ALS-mutation gene carriers compared to sixteen controls. Using human control primary myotubes, we further investigated the potential contribution of cholesterol dyshomeostasis to reliance on mitochondrial fatty acid. We found that cholesterol accumulates in the skeletal muscle of ALS patients and that cholesterol overload significantly correlates with disease severity evaluated by the Revised ALS Functional Rating Scale. These defects are associated with overexpression of the genes of the lysosomal cholesterol transporters Niemann-Pick type C1 (NPC1) and 2 (NPC2), which are required for cholesterol transfer from late endosomes/lysosomes to cellular membranes. Most notably, a significant increase in NPC2 mRNA levels could be detected in muscle samples from asymptomatic ALS-mutation carriers, long before disease onset. We found that filipin-stained unesterified cholesterol accumulated in the lysosomal compartment in ALS muscle samples, suggesting dysfunction of the NPC1/2 system. Accordingly, we report here that experimental NPC1 inhibition or lysosomal pH alteration in human primary myotubes was sufficient to induce the overexpression of NPC1 and NPC2 mRNA. Finally, acute NPC1 inhibition in human control myotubes induced a shift towards a preferential use of fatty acids, thus reproducing the metabolic defect characteristic of ALS muscle. We conclude that cholesterol homeostasis is dysregulated in ALS muscle from the presymptomatic stage. Targeting NPC1/2 dysfunction may be a new therapeutic strategy for ALS to restore muscle energy metabolism and slow motor symptom progression.

Effect of Early Ciprofloxacin Administration on Growth Performance, Meat Quality, Food Safety, and Metabolomic Profiles in Xueshan Chickens.

To investigate the effects of early administration of ciprofloxacin (CIP) on Xueshan chickens, in this study Xueshan chickens were measured for growth performance, tested for drug residues, evaluated for meat quality, and muscle metabolism changes were explored using a non-target metabolomics approach. Experimental findings revealed that early CIP use did not significantly impact the overall growth rate of Xueshan chickens (p > 0.05). However, notable alterations in meat quality were observed: the CIP-treated group exhibited a significant decrease in muscle pH (pH1 and pH24) and a marked increase in drip loss and moisture content (p > 0.05). No CIP residues were detected in muscle tissue. Untargeted metabolomics analyses unveiled significant alterations in the metabolic profile of market-age chickens following CIP treatment. Both functional enrichment and metabolic network analyses indicated significant effects on the ko01120 (microbial metabolism in diverse environments) and ko00350 (tyrosine metabolism) pathways, implying that CIP treatment may influence chicken meat quality by modulating microbial communities and amino acid metabolism. This study provides a crucial foundation for understanding the impact of antibiotics on meat quality and metabolism in poultry production, offering scientific insights for optimizing antibiotic-use strategies and safeguarding poultry product quality.

Thermotherapy has Sexually Dimorphic Responses in APP/PS1 Mice.

A thermoregulatory decline occurs with age due to changes in muscle mass, vasoconstriction, and metabolism that lowers core body temperature (Tc). Although lower Tc is a biomarker of successful aging, we have previously shown this worsens cognitive performance in the APP/PS1 mouse model of Alzheimer's disease (AD) [1]. We hypothesized that elevating Tc with thermotherapy would improve metabolism and cognition in APP/PS1 mice. From 6-12 months of age, male and female APP/PS1 and C57BL/6 mice were chronically housed at 23 or 30°C. At 12 months of age, mice were assayed for insulin sensitivity, glucose tolerance, and spatial cognition. Plasma, hippocampal, and peripheral (adipose, hepatic, and skeletal muscle) samples were procured postmortem and tissue-specific markers of amyloid accumulation, metabolism, and inflammation were assayed. Chronic 30°C exposure increased Tc in all groups except female APP/PS1 mice. All mice receiving thermotherapy had either improved glucose tolerance or insulin sensitivity, but the underlying processes responsible for these effects varied across sexes. In males, glucose regulation was influenced predominantly by hormonal signaling in plasma and skeletal muscle glucose transporter 4 expression, whereas in females, this was modulated at the tissue level. Thermotherapy improved spatial navigation in male C57BL/6 and APP/PS1 mice, with the later attributed to reduced hippocampal soluble amyloid-β (Aβ)42. Female APP/PS1 mice exhibited worse spatial memory recall after chronic thermotherapy. Together, the data highlights the metabolic benefits of passive thermotherapy, but future studies are needed to determine therapeutic benefits for those with AD.

Mechanism of skeletal muscle atrophy by muscle fiber types in male rats under long-term fasting stress

Fasting induces metabolic changes in muscles, which are differentiated by muscle fiber type. In this study, the mechanism of fasting-induced muscle atrophy in rats was examined to determine the differences between muscle fiber types in energy production. Fasting for 96 h did not alter the weight of the soleus (SOL), a fiber type I muscle, but did significantly reduce the weight of gastrocnemius (GM), a fiber type II muscle. GM, SOL and blood pregnenolone and testosterone levels decreased under fasting, which induced energy deprivation, whereas corticosterone (CORT) levels significantly increased. However, the expression of 3β-HSD and P45011β in GM was unaffected by fasting. The decrease in GM weight may be due to decreased levels of testosterone and reduced synthesis of mammalian target of rapamycin (mTOR). Significant increases in CORT both GM and SOL were associated with increases in the amount of branched-chain amino acids available for energy production. However, decreased levels of mTOR and IGF1 and increased levels of CORT and IL-6 in SOL suggest that GM proteolysis was followed by SOL proteolysis for additional energy production. In conclusion, IGF1 levels decreased significantly in SOL, whereas those of IL-6 significantly increased in SOL and blood but decreased in GM. Blood branched-chain amino acids (BCAA) levels were unaffected due to fasting, whereas an increase was noted in the levels of BCAA in GM and SOL. These results show that fasting for 96 h restricts energy supply, producing fast-twitch muscle atrophy followed by slow-twitch muscle atrophy.

Consistent changes in muscle metabolism underlie dive performance across multiple lineages of diving ducks.

Diving animals must sustain high activity with limited O2 stores to successfully capture prey. Studies suggest that increasing body O2 stores supports breath-hold diving, but less is known about metabolic specializations that underlie underwater locomotion. We measured maximal activities of 10 key enzymes in locomotory muscles (gastrocnemius and pectoralis) to identify biochemical changes associated with diving in pathways of oxidative and substrate-level phosphorylation and compared them across three groups of ducks-the longest diving sea ducks (eight spp.), the mid-tier diving pochards (three spp.) and the non-diving dabblers (five spp.). Relative to dabblers, both diving groups had increased activities of succinate dehydrogenase and cytochrome c oxidase, and sea ducks further showed increases in citrate synthase (CS) and hydroxyacyl-CoA dehydrogenase (HOAD). Both diving groups had relative decreases in capacity for anaerobic metabolism (lower ratio of lactate dehydrogenase to CS), with sea ducks also showing a greater capacity for oxidative phosphorylation and lipid oxidation (lower ratio of pyruvate kinase to CS, higher ratio of HOAD to hexokinase). These data suggest that the locomotory muscles of diving ducks are specialized for sustaining high rates of aerobic metabolism, emphasizing the importance of body O2 stores for dive performance in these species.

The effect of a combination of functional electrical stimulation and cycle ergometer (FES-cycling) on physiological changes and functional ability in patients with ICU-acquired weakness

Intensive care unit-acquired weakness (ICU-AW) is the most common complication found in the intensive care unit (ICU) patients, especially those on prolonged use of mechanical ventilation (MV). It is known to cause poor long-term outcomes, and early rehabilitation (ER) intervention has been proved to be useful in improving muscle strength, physical function, and quality of life of ICU survivors. Several obstacles, such as patients’ medical condition and limited availability of equipment or trained personnel, interfere with ER. Passive ER including functional electrical stimulation (FES) and cycling were found to be effective. The combination of FES with a cycle ergometer (FES cycling) can be implemented, but research on using this modality in the ICU is still limited. This review aimed at providing information on the use of FES cycling in ICU patients to explain its effect on physiological changes and functional abilities. The physiological effects of FES cycling are obtained through local metabolic changes in muscles due to FES and increased cardiovascular responses due to muscle contraction during cycling. Its effects on muscle strength, cross-section area, days free of MV, mobilization, cognitive ability, delirium, and quality of life were positive, and only rarely adverse events occurred during the intervention. To conclude, the use of FES cycling in the prevention and treatment of ICU-AW can be considered since this modality causes positive physiological effects and has proven safe.
 Abbreviations: EM – Early Mobilization; ER- early rehabilitation; FES - functional electrical stimulation; ICU-AW - Intensive Care Unit-Acquired Weakness; MV - mechanical ventilation; NMBA - neuromuscular blocking agents; PICS - post-intensive care syndrome; NMES - neuromuscular electrical stimulation;
 Key words: Electrical Stimulation; Intensive Care Unit; Muscle Contraction; Muscle Strength; Quality of Life
 Citation: Nazir A. The effect of a combination of functional electrical stimulation and cycle ergometer (FES-cycling) on physiological changes and functional ability in patients with ICU-acquired weakness. Anaesth. pain intensive care 2023;27(5):599−606; DOI: 10.35975/apic.v27i5.2315
 Received: July 03, 2023; Reviewed & Accepted: August 18, 2023

Rutin Prevents Dexamethasone-Induced Muscle Loss in C2C12 Myotube and Mouse Model by Controlling FOXO3-Dependent Signaling

One of the causes of sarcopenia is that homeostasis between anabolism and catabolism breaks down due to muscle metabolism changes. Rutin has shown antioxidant and anti-inflammatory effects in various diseases, but there are few studies on the effect on muscle loss with aging. The effect of rutin on muscle loss was evaluated using dexamethasone-induced muscle loss C2C12 myoblast and mouse model. In the group treated with dexamethasone, the muscle weight of gastrocnemius (GA), tibialis anterior (TA), and extensor digitorum longus (EDL) in the mouse model were significantly decreased (p < 0.0001 in GA, p < 0.0001 in TA, and p < 0.001 in EDL) but recovered (p < 0.01 in GA, p < 0.0001 in TA, and p < 0.01 in EDL) when treated with rutin. MAFbx, MuRF1, and FOXO3 protein expression of C2C12 myoblast were significantly increased (p < 0.01 in MAFbx, p < 0.01 in MuRF1, and p < 0.01 in FOXO3) when treated with dexamethasone, but it was recovered (p < 0.01 in MAFbx, p < 0.01 in MuRF1, and p < 0.01 in FOXO3) when rutin was treated. In addition, MAFbx and FOXO3 protein expression in GA of mouse model was significantly increased (p < 0.0001 in MAFbx and p < 0.001 in FOXO3) when treated with dexamethasone, but it was also recovered (p < 0.01 in MAFbx and p < 0.001 in FOXO3) when rutin was treated. The present study shows that rutin blocks the FOXO3/MAFbx and FOXO3/MuRf1 pathways to prevent protein catabolism. Therefore, rutin could be a potential agent for muscle loss such as sarcopenia through the blocking ubiquitin-proteasome pathway associated with catabolic protein degradation.

Supplementation-induced change in muscle carnosine is paralleled by changes in muscle metabolism, protein glycation and reactive carbonyl species sequestering.

Carnosine is a performance-enhancing food supplement with a potential to modulate muscle energy metabolism and toxic metabolites disposal. In this study we explored interrelations between carnosine supplementation (2 g/day, 12 weeks) induced effects on carnosine muscle loading and parallel changes in (i) muscle energy metabolism, (ii) serum albumin glycation and (iii) reactive carbonyl species sequestering in twelve (M/F=10/2) sedentary, overweight-to-obese (BMI: 30.0+/-2.7 kg/m2) adults (40.1+/-6.2 years). Muscle carnosine concentration (Proton Magnetic Resonance Spectroscopy; 1H-MRS), dynamics of muscle energy metabolism (Phosphorus Magnetic Resonance Spectroscopy; 31P-MRS), body composition (Magnetic Resonance Imaging; MRI), resting energy expenditure (indirect calorimetry), glucose tolerance (oGTT), habitual physical activity (accelerometers), serum carnosine and carnosinase-1 content/activity (ELISA), albumin glycation, urinary carnosine and carnosine-propanal concentration (mass spectrometry) were measured. Supplementation-induced increase in muscle carnosine was paralleled by improved dynamics of muscle post-exercise phosphocreatine recovery, decreased serum albumin glycation and enhanced urinary carnosine-propanal excretion (all p<0.05). Magnitude of supplementation-induced muscle carnosine accumulation was higher in individuals with lower baseline muscle carnosine, who had lower BMI, higher physical activity level, lower resting intramuscular pH, but similar muscle mass and dietary protein preference. Level of supplementation-induced increase in muscle carnosine correlated with reduction of protein glycation, increase in reactive carbonyl species sequestering, and acceleration of muscle post-exercise phosphocreatine recovery.

The Role of Mitophagy in Skeletal Muscle Damage and Regeneration.

Mitochondria are cellular organelles that play an essential role in generating the chemical energy needed for the biochemical reactions in cells. Mitochondrial biogenesis, i.e., de novo mitochondria formation, results in enhanced cellular respiration, metabolic processes, and ATP generation, while autophagic clearance of mitochondria (mitophagy) is required to remove damaged or useless mitochondria. The balance between the opposing processes of mitochondrial biogenesis and mitophagy is highly regulated and crucial for the maintenance of the number and function of mitochondria as well as for the cellular homeostasis and adaptations to metabolic demands and extracellular stimuli. In skeletal muscle, mitochondria are essential for maintaining energy homeostasis, and the mitochondrial network exhibits complex behaviors and undergoes dynamic remodeling in response to various conditions and pathologies characterized by changes in muscle cell structure and metabolism, such as exercise, muscle damage, and myopathies. In particular, the involvement of mitochondrial remodeling in mediating skeletal muscle regeneration following damage has received increased attention, as modifications in mitophagy-related signals arise from exercise, while variations in mitochondrial restructuring pathways can lead to partial regeneration and impaired muscle function. Muscle regeneration (through myogenesis) following exercise-induced damage is characterized by a highly regulated, rapid turnover of poor-functioning mitochondria, permitting the synthesis of better-functioning mitochondria to occur. Nevertheless, essential aspects of mitochondrial remodeling during muscle regeneration remain poorly understood and warrant further characterization. In this review, we focus on the critical role of mitophagy for proper muscle cell regeneration following damage, highlighting the molecular mechanisms of the mitophagy-associated mitochondrial dynamics and network reformation.

Exon-intron split analysis reveals posttranscriptional regulatory signals induced by high and low n-6/n-3 polyunsaturated fatty acid ratio diets in piglets.

Polyunsaturated fatty acids (PUFA), such as omega-6 (n-6) and omega-3 (n-3), play a vital role in nutrient metabolism, inflammatory response, and gene regulation. microRNAs (miRNA), which can potentially degrade targeted messenger RNAs (mRNA) and/or inhibit their translation, might play a relevant role in PUFA-related changes in gene expression. Although differential expression analyses can provide a comprehensive picture of gene expression variation, they are unable to disentangle when in the mRNA life cycle the regulation of expression is taking place, including any putative functional miRNA-driven repression. To capture this, we used an exon-intron split analysis (EISA) approach to account for posttranscriptional changes in response to extreme values of n-6/n-3 PUFA ratio. Longissimus dorsi muscle samples of male and female piglets from sows fed with n-6/n-3 PUFA ratio of 13:1 (SOY) or 4:1 (LIN), were analyzed in a bidirectional contrast (LIN vs. SOY, SOY vs. LIN). Our results allowed the identification of genes showing strong posttranscriptional downregulation signals putatively targeted by significantly upregulated miRNA. Moreover, we identified genes primarily involved in the regulation of lipid-related metabolism and immune response, which may be associated with the pro- and anti-inflammatory functions of the n-6 and n-3 PUFA, respectively. EISA allowed us to uncover regulatory networks complementing canonical differential expression analyses, thus providing a more comprehensive view of muscle metabolic changes in response to PUFA concentration.

Pork quality traits and associated muscle metabolic changes in pigs under chronic prenatal and postnatal heat stress.

Chronic heat stress (HS) is a major concern affecting pig growth performance and metabolism, with potential consequences on carcass and meat quality traits. The objective of this study was to assess the influence of prenatal (PE) and growing (GE) thermal environments, and their combination, on muscle metabolism, carcass characteristics, and pork quality. From 6 to 109 d of gestation, 12 sows (1 per block) were kept under thermoneutral (TN) conditions (cyclic 18 to 24 °C; PTN) and 12 sows under chronic HS (cyclic 28 to 34 °C; PHS). Two female offspring per sow were selected based on body weight at weaning, for a total of 48 female pigs (12 blocks of 2 sisters from each PE), and one sister was placed in each GE. Gilts were housed from 82 to 140 d of age under cyclic GTN (18 to 24 °C; n = 24) or GHS (28 to 34 °C; n = 24) environments. Data were analyzed using a mixed model including PE, GE, and PE × GE interaction as main effects, and sire, sow within PE, pen within PE × GE, and slaughter day (for plasma, muscle, and meat traits) as random effects. No significant PE × GE interaction was found on any trait under study (P ≥ 0.05). Prenatal HS did not affect growth performance and carcass traits (P ≥ 0.05). Compared with GTN, GHS pigs had lower average daily feed intake, average daily gain, and hot carcass weight (P < 0.01), but similar carcass lean meat content (P ≥ 0.05). Prenatal HS had scarce effects on pork quality, with only higher a* and C* values (P < 0.05) in the Gluteus superficialis. Growing HS led to a higher pH 24 h (P < 0.05) in the Longissimus thoracis et lumborum (LTL) and ham muscles, and higher meat quality index in the ham muscles. In contrast, quality traits of the Semispinalis capitis (SC) were not affected by either PE or GE (P > 0.05). Except a tendency for a higher citrate synthase activity in the SC (P = 0.065), PHS did not affect muscle metabolism. Growing HS induced muscle-specific metabolic responses, with reduced glycolytic potential (P < 0.01) and metabolic enzyme activities (P < 0.05) in the glycolytic LTL, but not in the oxidative SC (P > 0.05). Plasma glucose content at slaughter was lower in the GHS compared with GTN pigs (P = 0.002), indicating an altered energy metabolism in pigs under GHS. Altogether, growing HS altered growth without affecting carcass traits, but improved technological quality of loin and ham. Prenatal HS, alone or combined with GHS, had limited or even no effect on carcass and pork quality.

RNA-Seq exploration of the influence of stress on meat quality in Spanish goats

Studies exploring the transcriptome of stress and its effects on meat quality are very limited, particularly in goats. Fifty-four male Spanish goats (8-mo old; BW = 29.7 ± 2.03 kg) were randomly subjected to one of three treatments (TRT; n = 18 goats/treatment): (1) transported for 180 min, (2) transported for 30 min, or (3) held in pens (control) to analyze the transcriptome of stress and meat quality in goats using RNA-seq technology. Blood samples were collected before and after treatment, and meat samples were collected after humane slaughter for stress hormone, meat quality (Longissimus dorsi), and transcriptomic analysis. Plasma epinephrine concentrations were higher (P < 0.01) in 180 min and 30 min groups compared to the control group; however, norepinephrine concentrations were not affected by the treatment. Muscle glycogen concentrations (15 min postmortem) were lower (P < 0.01) in both 30 min and 180 min groups compared to the control group. Calpastatin levels were higher (P < 0.01) in 180 min and 30 min groups than the control group. Warner–Bratzler shear force values of loin chops were the highest in the 180 min group (4 ± 0.15, kg), lowest in the control group (3.51 ± 0.10, kg), and intermediate in the 30 min group (3.78 ± 0.09, kg; P < 0.01) both at day 1 and day 6 aging time. Additionally, desmin levels of day 6 samples were lowest in the control group, highest in 180 min group, and intermediate in 30 min group (P < 0.05). RNA-seq results showed that a total of 10,633 genes were differentially expressed (5194 up regulated; 5439 down regulated) among all comparisons (blood and day 1 and day 6 muscle samples). Among these differentially expressed genes (DEGs), KLF9, AMPK, FOXO3, PTX3, GADD45, PTPN1, CASP7, MAPK4, HSPA12A, and JAK-STAT were probably associated with the effects of stress on skeletal muscle proteins and involved in biological process such as cellular response to corticosteroid stimulus, endoplasmic reticulum stress, insulin resistance, DNA repair, apoptosis, MAPK cascade and regulation of proteolysis. The KEGG analysis revealed that AMPK and JAK-SAT signaling pathways and autophagy were among the top 20 enriched pathways in our treatment comparisons. The results provide an understanding of the genes and pathways involved in stress responses and related changes in postmortem muscle metabolism and meat quality characteristics in goats.

Effect of electromyostimulation training on intramuscular fat accumulation determined by ultrasonography in older adults.

PurposeElectromyostimulation (EMS) induces a short-term change in muscle metabolism, and EMS training induces long-term improvements of muscle atrophy and function. However, the effects of EMS training on intramuscular fat in older adults are still poorly known. The purpose of this study was to examine whether the intramuscular fat index and biochemical parameters change with EMS training of the quadriceps femoris muscles in older adults.MethodsNineteen non-obese older men and women performed EMS training of the quadriceps femoris for 12 weeks (3 times/week; single session for 30 min). The intramuscular fat content index was estimated by echo intensity of the vastus lateralis and rectus femoris muscles on ultrasonography, and muscle thickness was also measured. Muscle strength was assessed as the maximal voluntary contraction during isometric knee extension. Echo intensity, muscle thickness, and muscle strength were measured before and after EMS training. A rested/fasting blood samples were collected before and after EMS training for measuring plasma glucose, insulin, free fatty acid, triglyceride, and interleukin-6 concentrations. To examine the acute effect of a single-EMS session on biochemical parameters, blood samples were taken before and after the EMS session.ResultsEMS training did not significantly change echo intensity in muscles, muscle thickness, muscle strength, or biochemical parameters. Regarding the acute effect on blood lipid concentrations, a single-EMS session increased free fatty acid and glucose concentrations.ConclusionEMS sessions had an acute effect of increasing free fatty acid and glucose concentrations, but EMS training intervention did not improve intramuscular fat content.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00421-022-05074-3.

The Effects of Exercise Training on Glucose Homeostasis and Muscle Metabolism in Type 1 Diabetic Female Mice.

Although exercise training is an important recommendation for the management of type 1 diabetes (T1D), most of the available research studies predominantly focus on male subjects. Given the importance of sex as a biological variable, additional studies are required to improve the knowledge gap regarding sex differences in T1D research. Therefore, the purpose of this study was to examine the role of exercise training in mediating changes in glucose homeostasis and skeletal muscle metabolism in T1D female mice. Female mice were injected with streptozotocin (STZ) to induce T1D. Two weeks after STZ injection, control (CON) and STZ mice were exercise trained on a treadmill for 4 weeks. Aerobic exercise training failed to improve glucose tolerance, prevent the decrease in body weight and adipose tissue mass, or attenuate muscle atrophy in T1D female mice. However, insulin sensitivity was improved in T1D female mice after exercise training. Aerobic exercise training maintained skeletal muscle triglyceride content but did not prevent depletion of skeletal muscle or liver glycogen in T1D mice. Gene expression analysis suggested that T1D resulted in decreased glucose transport, decreased ketone body oxidation, and increased fatty acid metabolism in the skeletal muscle, which was not altered by exercise training. These data demonstrate that 4 weeks of aerobic exercise training of a moderate intensity is insufficient to counteract the negative effects of T1D in female mice, but does lead to an improvement in insulin sensitivity.

AMPK activation is sufficient to increase skeletal muscle glucose uptake and glycogen synthesis but is not required for contraction-mediated increases in glucose metabolism

The AMP-activated protein kinase (AMPK) is a cellular sensor of energetics and when activated in skeletal muscle during contraction can impart changes in skeletal muscle metabolism. Therapeutics that selectively activate AMPK have been developed to lower glucose levels through increased glucose disposal rates as an approach to abrogate the hyperglycemic state of diabetes; however, the metabolic fate of glucose following AMPK activation remains unclear. We have used a combination of in vivo evaluation of glucose homeostasis and ex vivo skeletal muscle incubation to systematically evaluate metabolism following pharmacological activation of AMPK with PF-739, comparing this with AMPK activation through sustained intermittent electrical stimulation of contraction. These methods to activate AMPK result in increased glucose uptake but divergent metabolism of glucose: pharmacological activation results in increased glycogen accumulation while contraction-induced glucose uptake results in increased lactate formation and glucose oxidation. These results provide additional evidence to support a role for AMPK in control of skeletal muscle metabolism and additional insight into the potential for AMPK stimulation with small molecule direct activators.

Metabolomic profiling reveals muscle metabolic changes following iliac arteriovenous fistula creation in mice.

End-stage kidney disease, the most advanced stage of chronic kidney disease (CKD), requires renal replacement therapy or kidney transplant to sustain life. To accomplish durable dialysis access, the creation of an arteriovenous fistula (AVF) has emerged as a preferred approach. Unfortunately, a significant proportion of patients that receive an AVF experience some form of hand dysfunction; however, the mechanisms underlying these side effects are not understood. In this study, we used nuclear magnetic resonance spectroscopy to investigate the muscle metabolome following iliac AVF placement in mice with CKD. To induce CKD, C57BL6J mice were fed an adenine-supplemented diet for 3 wk and then randomized to receive AVF or sham surgery. Two weeks following surgery, the quadriceps muscles were rapidly dissected and snap frozen for metabolite extraction and subsequent nuclear magnetic resonance analysis. Principal component analysis demonstrated clear separation between groups, confirming a unique metabolome in mice that received an AVF. AVF creation resulted in reduced levels of creatine, ATP, and AMP as well as increased levels of IMP and several tricarboxylic acid cycle metabolites suggesting profound energetic stress. Pearson correlation and multiple linear regression analyses identified several metabolites that were strongly linked to measures of limb function (grip strength, gait speed, and mitochondrial respiration). In summary, AVF creation generates a unique metabolome profile in the distal skeletal muscle indicative of an energetic crisis and myosteatosis.NEW & NOTEWORTHY Creation of an arteriovenous fistula (AVF) is the preferred approach for dialysis access, but some patients experience hand dysfunction after AVF creation. In this study, we provide a detailed metabolomic analysis of the limb muscle in a murine model of AVF. AVF creation resulted in metabolite changes associated with an energetic crisis and myosteatosis that associated with limb function.

Could SGLT2 Inhibitors Improve Exercise Intolerance in Chronic Heart Failure?

Despite the constant improvement of therapeutical options, heart failure (HF) remains associated with high mortality and morbidity. While new developments in guideline-recommended therapies can prolong survival and postpone HF hospitalizations, impaired exercise capacity remains one of the most debilitating symptoms of HF. Exercise intolerance in HF is multifactorial in origin, as the underlying cardiovascular pathology and reactive changes in skeletal muscle composition and metabolism both contribute. Recently, sodium-related glucose transporter 2 (SGLT2) inhibitors were found to improve cardiovascular outcomes significantly. Whilst much effort has been devoted to untangling the mechanisms responsible for these cardiovascular benefits of SGLT2 inhibitors, little is known about the effect of SGLT2 inhibitors on exercise performance in HF. This review provides an overview of the pathophysiological mechanisms that are responsible for exercise intolerance in HF, elaborates on the potential SGLT2-inhibitor-mediated effects on these phenomena, and provides an up-to-date overview of existing studies on the effect of SGLT2 inhibitors on clinical outcome parameters that are relevant to the assessment of exercise capacity. Finally, current gaps in the evidence and potential future perspectives on the effects of SGLT2 inhibitors on exercise intolerance in chronic HF are discussed.

O107 Endotoxaemia rapidly impacts on skeletal muscle mrna expression under conditions of controlled nutrient availability in humans

Abstract Introduction Inflammation induces changes in muscle protein turnover and mass and dampens insulin stimulated glucose disposal and oxidation. Limited information is available regarding the molecular regulation of these events. We determined the acute effects of lipopolysaccharide (LPS) infusion on targeted muscle mRNA expression. Methods Seven healthy, males (age 21.9±0.6 yrs, BMI 23.4±1.2 kg.m-2) participated in this ethically approved randomised crossover design study. On 2 occasions separated by &amp;gt;2 weeks, subjects underwent a 4h hyperinsulinaemic euglycaemic clamp combined with a primed mixed amino-acid (6 g.h-1; to create a ‘fed-state’) infusion, immediately following bolus saline (control) or LPS (4 ng.kg-1) infusion. Vastus lateralis muscle biopsies were obtained at baseline, 120 and 240 min. Muscle mRNA expression was measured (191 targets deemed to be representative of insulin sensitivity, carbohydrate and fat metabolism, inflammation, and protein turnover) using microfluidics TaqMan array cards. Results Plasma [TNF alpha] was markedly elevated above control following 60 min of LPS infusion (P&amp;lt;0.05) and remained elevated. Following gene filtering (&amp;gt;1.5 fold change in muscle mRNA expression from baseline, P&amp;lt;0.05), Ingenuity Pathway Analysis identified several metabolic functions significantly altered from baseline after 120 and 240 min in control. The magnitude of change in each metabolic function (-log p value) and the size of each gene network was substantially greater after LPS. Conclusion Muscle mRNAs respond rapidly to insulin and amino acid infusion in humans, but the magnitude of response was greater in the presence of LPS and may underpin changes in muscle protein and fuel metabolism seen under these conditions. Take-home message Endotoxaemia acts rapidly (within 2 to 4 hours) to alter the expression levels of muscle mRNAs known to be intimately involved in the molecular regulation of muscle mass, insulin resistance and fuel oxidation in human volunteers under controlled conditions of insulin and nutrient availability. This may play a role in the changes in muscle metabolism seen under such conditions.

Metabolic therapy and its impact on lung respiratory function in patients with severe COVID-19

Background. Metabolic disorders, often detected in patients with severe COVID-19 infection, indicate the severity of the infection process and play an important role in the pathogenesis of the disease. Changes in muscle metabolism lead to weakness and reduced mobility of the diaphragm, which exacerbates the progression of respiratory failure.&#x0D; Aim. To evaluate the effect of a meglumine sodium succinate 1.5% solution on the dynamics of metabolic blood parameters and respiratory function of the lungs in patients with COVID-19.&#x0D; Material and methods. The observational prospective study included 105 patients with severe COVID-19 treated in the intensive care unit. As an infusion therapy, patients in the control group (n=54) received Ringer's solution, in the main group (n=51) 1.5% solution of meglumine sodium succinate. Infusion therapy was carried out for 11 days. All patients underwent standard laboratory tests. Diaphragm mobility was assessed using an ultrasound scanner. Intergroup comparisons were performed using the MannWhitney test, and intragroup dynamics were assessed using the KruskalWallis test.&#x0D; Results. Upon admission to the intensive care unit, in 36.2% of patients, the development of respiratory failure was accompanied by a decrease in the excursion of the right dome of the diaphragm to less than 1.7 cm, in 92.4% of patients the development of hyperglycemia and hyperlactatemia. By the 11th day of ongoing treatment, hyperglycemia persisted in 16.7% of patients in the control group and 3.9% of patients in the main group, hyperlactatemia in 53.7 and 9.8% of patients, respectively. Maintenance and then gradual restoration of diaphragm excursion in patients of the main group, a decrease in hypercapnia and a gradual increase in the pO2/FiO2 index were registered. Therapy with a solution of meglumine sodium succinate significantly reduced the duration of hospital treatment after transfer from the intensive care unit (p=0.007).&#x0D; Conclusion. The inclusion of a 1.5% solution of meglumine sodium succinate in the therapy of patients with severe COVID-19 can reduce the duration of metabolic disorders, which has a positive effect on the degree of respiratory dysfunction, diaphragmatic excursion depression and the treatment duration after transfer from the intensive care unit.

Longitudinal Changes in Skeletal Muscle Metabolism, Oxygen Uptake, and Myosteatosis During Cardiotoxic Treatment for Early-Stage Breast Cancer

BackgroundWhile cardiotoxic chemotherapy is known to negatively impact cardiac function and hemoglobin levels, the impact on skeletal muscle has been understudied among patients. The purpose was to longitudinally characterize myosteatosis (muscle fat), skeletal muscle metabolism, and oxygen (O2) consumption during cardiotoxic chemotherapy for breast cancer.Patients and MethodsThirty-four patients with stage I-III breast cancer were enrolled before trastuzumab-containing and/or anthracycline-containing chemotherapy. We used magnetic resonance imaging to non-invasively quantify thigh myosteatosis (fat-water imaging), and lower leg metabolism (31P spectroscopy), O2 consumption (custom techniques), and peak power output during single-leg plantarflexion exercise at pre-, mid-, end-chemotherapy, and 1-year. We also measured pulmonary VO2peak and maximal leg press strength.ResultsDuring chemotherapy, VO2peak and leg press strength decreased while peak plantarflexion power output was maintained. At mid-chemotherapy, hemoglobin decreased (16%) and lower leg blood flow increased (37%) to maintain lower leg O2 delivery; exercise Pi:PCr and myosteatosis increased. Between mid- and end-chemotherapy, lower leg O2 extraction (28%) and O2 consumption (21%) increased, while plantarflexion exercise efficiency (watts/O2 consumed) decreased. At one year, VO2peak and leg press strength returned to pre-chemotherapy levels, but lower leg exercise O2 extraction, consumption and Pi:PCr, and myosteatosis remained elevated.ConclusionLower leg skeletal muscle blood flow and O2 extraction adapt to compensate for chemotherapy-related hemoglobin reduction for small muscle mass exercise but are insufficient to maintain large muscle mass exercise (pulmonary VO2peak, leg press strength). The excess O2 required to perform work, increased Pi:PCr ratio and myosteatosis together suggest suppressed fat oxidation during chemotherapy.