Pleiotropic effects of an eQTL in the CELSR2/PSRC1/SORT1 cluster that associates with LDL-C and resting metabolic rate.

CONTEXT: The locus CELSR2-PSRC1-SORT1, a primary genetic signal for lipids, has recently been implicated in different metabolic processes. Our investigation identified its association with energy metabolism. OBJECTIVE: To determine biological mechanisms that govern diverse functions of this locus. METHODS: Genotypes for 491,265 variants in 7,000 clinically characterized American Indians were previously determined using a custom-designed array specific for this longitudinally studied American Indian population. Among the genotyped individuals, 5,205 had measures of fasting lipid levels and 509 had measures of resting metabolic rate (RMR) and substrate oxidation rate assessed through indirect calorimetry. A genome-wide association study (GWAS) for LDL-C levels identified a variant in CELSR2 and the molecular impact of this variant on gene expression was assessed in skeletal muscle biopsies from 207 participants, followed by functional validation in mouse myoblasts using a luciferase assay. RESULTS: A GWAS in American Indians identified rs12740374 in CELSR2 as the top signal for LDL-C levels (P = 1 × 10-22); further analysis of this variant identified an unexpected correlation with reduced RMR (effect = -44.3 kcal/day/minor-allele) and carbohydrate oxidation rate (effect = -5.21 mg/hour/kg-EMBS). Tagged variants showed a distinct linkage disequilibrium architecture in American Indians, highlighting a potential functional variant, rs6670347 (minor-allele frequency = 0.20). Positioned in the glucocorticoid receptor's core binding motif, rs6670347 is part of a skeletal muscle-specific enhancer. Human skeletal muscle transcriptome analysis showed CELSR2 as the most differentially expressed gene (P = 1.9 × 10-7), with the RMR-lowering minor allele elevating gene expression. Experiments in mouse myoblasts confirmed enhancer-based regulation of CELSR2 expression, dependent on glucocorticoids. Rs6670347 also associated with increased oxidative phosphorylation gene expression; CELSR2 as a regulator of these genes, suggests potential influence on energy metabolism through muscle oxidative capacity. CONCLUSION: Variants in the CELSR2/PSRC1/SORT1 locus exhibit tissue-specific effects on metabolic traits, with an independent role in muscle metabolism through glucocorticoid signaling.

A randomized translational study on protein- and glucose metabolism in skeletal muscles evaluated by gene-ontology, following preoperative oral carbohydrate loading compared to overnight peripheral parenteral nutrition (PPN) before major cancer surgery.

BACKGROUND: Effects of preoperative drinks on muscle metabolism are unclear despite general recommendations. The aim of the present study was therefore to compare metabolic effects of a preoperative oral nutrition drink, recommended by protocols for enhanced recovery after surgery (ERAS), compared to overnight preoperative peripheral total parenteral nutrition (PPN) on skeletal muscle metabolism in patients aimed at major gastrointestinal cancer surgery. METHODS: Patients were randomized, based on diagnosis and clinical characteristics, to receive either a commercial carbohydrate-rich nutrition drink (Drink); or overnight (12 h) peripheral parenteral nutrition (PPN) as study regimens; compared to isotone Ringer-acetate as Control regimen. Arterial blood- and abdominal muscle tissue specimens were collected at start of surgery. Blood chemistry included substrate- and hormone concentrations. Muscle mRNA transcript analyses were performed by microarray and evaluated for changes in gene activities by Gene Ontology algorithms. RESULTS: Patient groups were comparable in all measured preoperative assessments. The Nutrition Drink had significant metabolic alterations on muscle glucose metabolism (p < 0.05), without any significant effects on amino acid- and protein metabolism. PPN showed similar significant effects on glucose metabolism as Drinks (p < 0.05), but indicated also major positive effects on amino acid- (p < 0.001) and protein anabolism (p < 0.05), particularly by inhibition of muscle protein degradation, related to both ubiquitination of proteins and autophagy/lysosome pathways (p < 0.05). CONCLUSION: Conventional overnight preoperative PPN seems effective to induce and support improved muscle protein metabolism in patients aimed at major cancer surgery while preoperative oral carbohydrate loading, according to ERAS-protocols, was ineffective to improve skeletal muscle catabolism and should therefore not be recommended before major cancer surgery. Trial registration Clinical trials.gov: NCT05080816, Registered June 10th 2021- Retrospectively registered. https://clinicaltrials.gov/study/NCT05080816.

Skeletal Muscle Metabolism Is Dynamic during Porcine Postnatal Growth.

Skeletal muscle metabolism has implications for swine feed efficiency (FE); however, it remains unclear if the metabolic profile of skeletal muscle changes during postnatal growth. To assess the metabolic changes, samples were collected from the longissimus dorsi (LD, glycolytic muscle), latissimus dorsi (LAT, mixed muscle), and masseter (MS, oxidative muscle) at 20, 53, 87, 120, and 180 days of age from barrows. Muscles were assessed to determine the abundance of several metabolic enzymes. Lactate dehydrogenase (LDHα) decreased in all muscles from 20 to 87 d (p < 0.01), which may be attributed to the muscles being more glycolytic at weaning from a milk-based diet. Pyruvate carboxylase (PC) increased in all muscles at 53 d compared to the other time points (p < 0.01), while pyruvate dehydrogenase α 1 (PDHα1) increased at 87 and 180 d in MS compared to LD (p < 0.05), indicating that potential changes occur in pyruvate entry into the tricarboxylic acid (TCA) cycle during growth. Isolated mitochondria from each muscle were incubated with 13C-labeled metabolites to assess isotopomer enrichment patterns of TCA intermediates. Citrate M + 2 and M + 4 derived from [13C3]-pyruvate increased at 87 d in LAT and MS mitochondria compared to LD mitochondria (p < 0.05). Regardless of the muscle, citrate M+3 increased at 87 d compared to 20, 53, and 120 d, while 180 d showed intermediate values (p < 0.01). These data support the notion that pyruvate metabolism is dynamic during growth. Our findings establish a metabolic fingerprint associated with postnatal muscle hypertrophy.

Unlocking the Nexus of Sirtuins: A Comprehensive Review of Their Role in Skeletal Muscle Metabolism, Development, and Disorders.

The sirtuins constitute a group of histone deacetylases reliant on NAD+ for their activity that have gained recognition for their critical roles as regulators of numerous biological processes. These enzymes have various functions in skeletal muscle biology, including development, metabolism, and the body's response to disease. This comprehensive review seeks to clarify sirtuins' complex role in skeletal muscle metabolism, including glucose uptake, fatty acid oxidation, mitochondrial dynamics, autophagy regulation, and exercise adaptations. It also examines their critical roles in developing skeletal muscle, including myogenesis, the determination of muscle fiber type, regeneration, and hypertrophic responses. Moreover, it sheds light on the therapeutic potential of sirtuins by examining their impact on a range of skeletal muscle disorders. By integrating findings from various studies, this review outlines the context of sirtuin-mediated regulation in skeletal muscle, highlighting their importance and possible consequences for health and disease.

Exploring Multi-Tissue Alternative Splicing and Skeletal Muscle Metabolism Regulation in Obese- and Lean-Type Pigs.

Alternative splicing (AS) is a crucial mechanism in post-transcriptional regulation, contributing significantly to the diversity of the transcriptome and proteome. In this study, we performed a comprehensive AS profile in nine tissues obtained from Duroc (lean-type) and Luchuan (obese-type) pigs. Notably, 94,990 AS events from 14,393 genes were identified. Among these AS events, it was observed that 80% belonged to the skipped exon (SE) type. Functional enrichment analysis showed that genes with more than ten AS events were closely associated with tissue-specific functions. Additionally, the analysis of overlap between differentially alternative splicing genes (DSGs) and differentially expressed genes (DEGs) revealed the highest number of overlapped genes in the heart and skeletal muscle. The novelty of our study is that it identified and validated three genes (PYGM, MAPK11 and CAMK2B) in the glucagon signaling pathway, and their alternative splicing differences were highly significant across two pig breeds. In conclusion, our study offers novel insights into the molecular regulation of diverse tissue physiologies and the phenotypic differences between obese- and lean-type pigs, which are helpful for pig breeding.

Biomonitoring the skeletal muscle metabolic dysfunction in knee osteoarthritis in older adults: Is Jumpstart Nutrition® Supplementation effective?

Background: This study aimed to investigate the efficacy of Jumpstart Nutrition® dietary supplement (JNDS) for enhancing the skeletal muscle metabolism and function of older adults with knee osteoarthritis (KOA) by evaluating the biomarkers of aberrant levels of serum tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), C-reactive protein (CRP), creatine kinase-muscle (CK-MM), and aldolase-A (Aldo-A). Methods: This twelve-week registry included 54 patients treated with JNDS mainly comprised of calcium, phosphorus, vitamin-K2, coenzyme-Q10, boswellic acid, and curcumin mixed with soy and whey protein (experimental group) and 51 patients treated with symptomatic slow-acting drugs for osteoarthritis (SYSADOA) (control group) for KOA confirmed with radiological images. At week 0 and week 12 for both the groups evaluated, the non-fasting serum levels of TNF-α, IL-10, CRP, CK-MM, and Aldo-A by using appropriate kits. Results: At week-twelve, the respective values of area under the ROC curves of the studied biomarkers for pooled experimental cohorts were 0.928, 0.907, 0.908, 0.927, and 0.988 having the significance of accuracy (R-square):66.28%, 47.25%, 70.39%, 65.13%, and 68.00%, indicating a satisfactory treatment policy, their mean± SD, and risk ratio, all exhibited highly significant differences (p<0.0001) and KOA-gradation was upgraded between≥2 and ≥3 from≥4 as per the Kellgren-Lawrence scale compared to the control. Fewer patients had to use emergency medications (p<0.05). Conclusions: Results suggest that JNDS may be effectively used to strengthen the skeletal muscle metabolism and function of elderly patients with KOA confirmed with the stabilization of studied biomarkers as an alternative to the treatment of SYSAD correlated with ROC curves and the Kellgren-Lawrence scale.

Metabolic reprogramming underlies cavefish muscular endurance despite loss of muscle mass and contractility.

Physical inactivity is a scourge to human health, promoting metabolic disease and muscle wasting. Interestingly, multiple ecological niches have relaxed investment into physical activity, providing an evolutionary perspective into the effect of adaptive physical inactivity on tissue homeostasis. One such example, the Mexican cavefish Astyanax mexicanus, has lost moderate-to-vigorous activity following cave colonization, reaching basal swim speeds ~3.7-fold slower than their river-dwelling counterpart. This change in behavior is accompanied by a marked shift in body composition, decreasing total muscle mass and increasing fat mass. This shift persisted at the single muscle fiber level via increased lipid and sugar accumulation at the expense of myofibrillar volume. Transcriptomic analysis of laboratory-reared and wild-caught cavefish indicated that this shift is driven by increased expression of pparγ-the master regulator of adipogenesis-with a simultaneous decrease in fast myosin heavy chain expression. Ex vivo and in vivo analysis confirmed that these investment strategies come with a functional trade-off, decreasing cavefish muscle fiber shortening velocity, time to maximal force, and ultimately maximal swimming speed. Despite this, cavefish displayed a striking degree of muscular endurance, reaching maximal swim speeds ~3.5-fold faster than their basal swim speeds. Multi-omic analysis suggested metabolic reprogramming, specifically phosphorylation of Pgm1-Threonine 19, as a key component enhancing cavefish glycogen metabolism and sustained muscle contraction. Collectively, we reveal broad skeletal muscle changes following cave colonization, displaying an adaptive skeletal muscle phenotype reminiscent to mammalian disuse and high-fat models while simultaneously maintaining a unique capacity for sustained muscle contraction via enhanced glycogen metabolism.

Microbiota dysbiosis influences immune system and muscle pathophysiology of dystrophin-deficient mice.

Duchenne muscular dystrophy (DMD) is a progressive severe muscle-wasting disease caused by mutations in DMD, encoding dystrophin, that leads to loss of muscle function with cardiac/respiratory failure and premature death. Since dystrophic muscles are sensed by infiltrating inflammatory cells and gut microbial communities can cause immune dysregulation and metabolic syndrome, we sought to investigate whether intestinal bacteria support the muscle immune response in mdx dystrophic murine model. We highlighted a strong correlation between DMD disease features and the relative abundance of Prevotella. Furthermore, the absence of gut microbes through the generation of mdx germ-free animal model, as well as modulation of the microbial community structure by antibiotic treatment, influenced muscle immunity and fibrosis. Intestinal colonization of mdx mice with eubiotic microbiota was sufficient to reduce inflammation and improve muscle pathology and function. This work identifies a potential role for the gut microbiota in the pathogenesis of DMD.

Isolated murine skeletal muscles utilize pyruvate over glucose for oxidation.

INTRODUCTION: Fuel sources for skeletal muscle tissue include carbohydrates and fatty acids, and utilization depends upon fiber type, workload, and substrate availability. The use of isotopically labeled substrate tracers combined with nuclear magnetic resonance (NMR) enables a deeper examination of not only utilization of substrates by a given tissue, but also their contribution to tricarboxylic acid (TCA) cycle intermediates. OBJECTIVES: The goal of this study was to determine the differential utilization of substrates in isolated murine skeletal muscle, and to evaluate how isopotomer anlaysis provided insight into skeletal muscle metabolism. METHODS: Isolated C57BL/6 mouse hind limb muscles were incubated in oxygenated solution containing uniformly labeled 13C6 glucose, 13C3 pyruvate, or 13C2 acetate at room temperature. Isotopomer analysis of 13C labeled glutamate was performed on pooled extracts of isolated soleus and extensor digitorum longus (EDL) muscles. RESULTS: Pyruvate and acetate were more avidly consumed than glucose with resultant increases in glutamate labeling in both muscle groups. Glucose incubation resulted in glutamate labeling, but with high anaplerotic flux in contrast to the labeling by pyruvate. Muscle fiber type distinctions were evident by differences in lactate enrichment and extent of substrate oxidation. CONCLUSION: Isotope tracing experiments in isolated muscles reveal that pyruvate and acetate are avidly oxidized by isolated soleus and EDL muscles, whereas glucose labeling of glutamate is accompanied by high anaplerotic flux. We believe our results may set the stage for future examination of metabolic signatures of skeletal muscles from pre-clinical models of aging, type-2 diabetes and neuromuscular disease.

Aerobic training increases mitochondrial respiratory capacity in human skeletal muscle stem cells from sedentary individuals.

The impact of aerobic training on human skeletal muscle cell (HSkMC) mitochondrial metabolism is a significant research gap, critical to understanding the mechanisms by which exercise augments skeletal muscle metabolism. We therefore assessed mitochondrial content and capacity in fully differentiated CD56+ HSkMCs from lean active (LA) and sedentary individuals with obesity (OS) at baseline, as well as lean/overweight sedentary individuals (LOS) at baseline and following an 18-day aerobic training intervention. Participants had in vivo skeletal muscle PCr recovery rate by 31P-MRS (mitochondrial oxidative kinetics) and cardiorespiratory fitness (V̇o2max) assessed at baseline. Biopsies of the vastus lateralis were performed for the isolation of skeletal muscle stem cells. LOS individuals repeated all assessments posttraining. HSkMCs were evaluated for mitochondrial respiratory capacity by high-resolution respirometry. Data were normalized to two indices of mitochondrial content (CS activity and OXPHOS protein expression) and a marker of total cell count (quantity of DNA). LA individuals had significantly higher V̇o2max than OS and LOS-Pre training; however, no differences were observed in skeletal muscle mitochondrial capacity, nor in carbohydrate- or fatty acid-supported HSkMC respiratory capacity. Aerobic training robustly increased in vivo skeletal muscle mitochondrial capacity of LOS individuals, as well as carbohydrate-supported HSkMC respiratory capacity. Indices of mitochondrial content and total cell count were similar among the groups and did not change with aerobic training. Our findings demonstrate that bioenergetic changes induced with aerobic training in skeletal muscle in vivo are retained in HSkMCs in vitro without impacting mitochondrial content, suggesting that training improves intrinsic skeletal muscle mitochondrial capacity.

Mechanosensors control skeletal muscle mass, molecular clocks, and metabolism.

BACKGROUND: Skeletal muscles (SkM) are mechanosensitive, with mechanical unloading resulting in muscle-devastating conditions and altered metabolic properties. However, it remains unexplored whether these atrophic conditions affect SkM mechanosensors and molecular clocks, both crucial for their homeostasis and consequent physiological metabolism. METHODS: We induced SkM atrophy through 14 days of hindlimb suspension (HS) in 10 male C57BL/6J mice and 10 controls (CTR). SkM histology, gene expressions and protein levels of mechanosensors, molecular clocks and metabolism-related players were examined in the m. Gastrocnemius and m. Soleus. Furthermore, we genetically reduced the expression of mechanosensors integrin-linked kinase (Ilk1) and kindlin-2 (Fermt2) in myogenic C2C12 cells and analyzed the gene expression of mechanosensors, clock components and metabolism-controlling genes. RESULTS: Upon hindlimb suspension, gene expression levels of both core molecular clocks and mechanosensors were moderately upregulated in m. Gastrocnemius but strongly downregulated in m. Soleus. Upon unloading, metabolism- and protein biosynthesis-related genes were moderately upregulated in m. Gastrocnemius but downregulated in m. Soleus. Furthermore, we identified very strong correlations between mechanosensors, metabolism- and circadian clock-regulating genes. Finally, genetically induced downregulations of mechanosensors Ilk1 and Fermt2 caused a downregulated mechanosensor, molecular clock and metabolism-related gene expression in the C2C12 model. CONCLUSIONS: Collectively, these data shed new lights on mechanisms that control muscle loss. Mechanosensors are identified to crucially control these processes, specifically through commanding molecular clock components and metabolism.

Mechanisms by which smoothelin-like protein 1 reverses insulin resistance in myotubules and mice.

Insulin resistance (InR) is manifested in skeletal muscle by decreased insulin-stimulated glucose uptake due to impaired insulin signaling and multiple post-receptor intracellular defects. Chronic glucose-induced insulin resistance leads to the activation of Ser/Thr kinases and elevated phosphorylation of insulin receptor substrate 1 (IRS1) on Ser residues. Phosphorylation of IRS1 triggers the dissociation of IRS1 and its downstream effector, phosphatidylinositol 3-kinase. In the present study, we provide evidence for the insulin-sensitizing role of smoothelin-like protein 1 (SMTNL1) that is a ligand-dependent co-regulator of steroid receptors, predominantly the progesterone receptor. SMTNL1 was transiently overexpressed in insulin-resistant C2C12 myotubes. A proteome profiler array revealed that mTOR and Ser/Thr kinases were SMTNL1-dependent signaling pathways. In the presence of progesterone, overexpression was coupled to decreased Ser phosphorylation of IRS1 at Ser307, Ser318, and Ser612 residues. SMTNL1 also induced the expression and activity of the p85 subunit of PI3K. SMTNL1 regulated the expression of PKCε, which phosphorylates IRS1 at Ser318 residue. SMTNL1 also regulated ERK1/2 and JNK, which phosphorylate IRS1 at Ser612 and Ser307, respectively. Real-time metabolic measurements of oxygen consumption rate and extracellular acidification rate revealed that SMTNL1 improved glycolysis and promoted the utilization of alternative carbon fuels. SMTNL1 also rescued the mitochondrial respiration defect induced by chronic insulin exposure. Collectively, SMTNL1 plays a crucial role in maintaining the physiological ratio of Tyr/Ser IRS1 phosphorylation and attenuates the insulin-signaling cascade that contributes to impaired glucose disposal, which makes it a potential therapeutic target for improving InR.

Carnosine synthase deficiency in mice affects protein metabolism in skeletal muscle.

Carnosine and anserine are abundant peptides found in the skeletal muscle and nervous system in many vertebrates. Several in vitro and in vivo studies have demonstrate that exogenously administered carnosine improves exercise performance. Furthermore, carnosine is an antioxidant and antifatigue supplement. However, the physiological functions of endogenous carnosine and its related histidine-containing dipeptides in a living organism remain unclear. We aimed to clarify the physiological roles of endogenous carnosine by investigating the characteristics of carnosine synthase gene-deficient mice and the effects of carnosine on skeletal muscle protein metabolism. We discovered that carnosine and anserine were undetectable in the skeletal muscle of carnosine synthase knockout mice. We also quantified protein gene expression and enzyme levels in muscle protein metabolism. Gene and protein levels of the muscle protein synthesizer insulin-like growth factor-1 (IGF-1) and the degrading enzyme cathepsin B were markedly lower in carnosine synthase gene-deficient mice than those in wild-type mice. The amount of 3-methylhistidine (a marker for muscle proteolysis) in forced exercise and the weight of the gastrocnemius muscle were considerably lower in carnosine synthase gene-deficient mice than in wild-type mice. Consequently, we showed that carnosine deficiency affects weight maintenance and protein metabolism in skeletal muscle, suggesting that carnosine regulates skeletal muscle protein metabolism.

The circadian clock regulates metabolic responses to physical exercise.

It has been proposed for years that physical exercise ameliorates metabolic diseases. Optimal exercise timing in humans and mammals has indicated that circadian clocks play a vital role in exercise and body metabolism. Skeletal muscle metabolism exhibits a robust circadian rhythm under the control of the suprachiasmatic nucleus of the hypothalamus. Clock genes also control the development, differentiation, and function of skeletal muscles. In this review, we aimed to clarify the relationship between exercise, skeletal muscles, and the circadian clock. Health benefits can be attained by the scheduling of exercise at the best circadian time. Exercise therapy for metabolic diseases and cardiovascular health is a key adjuvant method. This review highlights the importance of exercise timing in maintaining healthy metabolism and circadian clocks.

Divergent serum metabolomic, skeletal muscle signaling, transcriptomic, and performance adaptations to fasted versus whey protein-fed sprint interval training.

Sprint interval training (SIT) is a time-efficient alternative to endurance exercise, conferring beneficial skeletal muscle metabolic adaptations. Current literature has investigated the nutritional regulation of acute and chronic exercise-induced metabolic adaptations in muscle following endurance exercise, principally comparing the impact of training in fasted and carbohydrate-fed (CHO) conditions. Alternative strategies such as exercising in low CHO, protein-fed conditions remain poorly characterized, specifically pertaining to adaptations associated with SIT. Thus, this study aimed to compare the metabolic and performance adaptations to acute and short-term SIT in the fasted state with preexercise hydrolyzed (WPH) or concentrated (WPC) whey protein supplementation. In healthy males, preexercise protein ingestion did not alter exercise-induced increases in PGC-1α, PDK4, SIRT1, and PPAR-δ mRNA expression following acute SIT. However, supplementation of WPH beneficially altered acute exercise-induced CD36 mRNA expression. Preexercise protein ingestion attenuated acute exercise-induced increases in muscle pan-acetylation and PARP1 protein content compared with fasted SIT. Acute serum metabolomic differences confirmed greater preexercise amino acid delivery in protein-fed compared with fasted conditions. Following 3 wk of SIT, training-induced increases in mitochondrial enzymatic activity and exercise performance were similar across nutritional groups. Interestingly, resting muscle acetylation status was downregulated in WPH conditions following training. Such findings suggest preexercise WPC and WPH ingestion positively influences metabolic adaptations to SIT compared with fasted training, resulting in either similar or enhanced performance adaptations. Future studies investigating nutritional modulation of metabolic adaptations to exercise are warranted to build upon these novel findings.NEW & NOTEWORTHY These are the first data to show the influence of preexercise protein on serum and skeletal muscle metabolic adaptations to acute and short-term sprint interval training (SIT). Preexercise whey protein concentrate (WPC) or hydrolysate (WPH) feeding acutely affected the serum metabolome, which differentially influenced acute and chronic changes in mitochondrial gene expression, intracellular signaling (acetylation and PARylation) resulting in either similar or enhanced performance outcomes when compared with fasted training.

Hydroxy Selenomethionine Improves Meat Quality through Optimal Skeletal Metabolism and Functions of Selenoproteins of Pigs under Chronic Heat Stress.

Chronic heat stress (CHS) induces metabolic changes in skeletal muscle from growth to maintenance that jeopardizes growth performance, carcass traits, and meat quality of pigs. We investigated the protective effect of dietary organic selenium (hydroxy-4-methylselenobutanoic acid, OH-SeMet) on CHS-induced skeletal muscle damages of growing pigs, and the corresponding responses of selenoproteins. A total of 40 ((Landrace ×Yorkshire) × Duroc) pigs with an average live weight of 49.64 ± 2.48 kg were used in this 4-week trial. Pigs were randomly allotted to 5 groups: The control group was raised on a basal diet in a thermoneutral environment (22 ± 2 °C); and four CHS groups were raised on a basal diet and supplemented with Se 0.0, 0.2, 0.4, and 0.6 mg/kg as OH-SeMet, respectively, in hyperthermal condition (33 ± 2 °C). CHS resulted in significant decrease of growth performance, carcass traits, and meat quality, which were associated with reduced (p < 0.05) serum alkaline phosphatase (ALP) and total superoxide dismutase (T-SOD) and increased (p < 0.05) serum creatine (CK), sarcous heat shock protein 70 (HSP70), glucokinase (GCK), phosphoenolpyruvate carboxykinase (PEPCK), and malondialdehyde (MDA) contents. Meanwhile, four metabolism-related genes and seven selenoprotein encoding genes were abnormally expressed in skeletal muscle. Dietary OH-SeMet addition partially alleviated the negative impact of CHS on carcass traits and improved meat quality. These improvements were accompanied by the increase in Se deposition, the anti-oxidative capacity of serum and muscle, and protein abundance of GPX1, GPX3, GPX4, and SELENOP. Supplementation with 0.6 mg Se/kg (OH-SeMet) restored the sarcous PEPCK, and 0.4 and 0.6 mg Se/kg (OH-SeMet) restored all abnormally expressed metabolism-related and selenoprotein encoding genes. In summary, dietary supplementation with OH-SeMet beyond Se requirement mitigated CHS-induced depression of carcass traits and meat quality of pigs associated with optimal skeletal metabolism, enhanced antioxidant capacity, and regulation of selenoproteins in skeletal muscle of pigs.

Integrated multiomics analysis identifies molecular landscape perturbations during hyperammonemia in skeletal muscle and myotubes.

Ammonia is a cytotoxic molecule generated during normal cellular functions. Dysregulated ammonia metabolism, which is evident in many chronic diseases such as liver cirrhosis, heart failure, and chronic obstructive pulmonary disease, initiates a hyperammonemic stress response in tissues including skeletal muscle and in myotubes. Perturbations in levels of specific regulatory molecules have been reported, but the global responses to hyperammonemia are unclear. In this study, we used a multiomics approach to vertically integrate unbiased data generated using an assay for transposase-accessible chromatin with high-throughput sequencing, RNA-Seq, and proteomics. We then horizontally integrated these data across different models of hyperammonemia, including myotubes and mouse and human muscle tissues. Changes in chromatin accessibility and/or expression of genes resulted in distinct clusters of temporal molecular changes including transient, persistent, and delayed responses during hyperammonemia in myotubes. Known responses to hyperammonemia, including mitochondrial and oxidative dysfunction, protein homeostasis disruption, and oxidative stress pathway activation, were enriched in our datasets. During hyperammonemia, pathways that impact skeletal muscle structure and function that were consistently enriched were those that contribute to mitochondrial dysfunction, oxidative stress, and senescence. We made several novel observations, including an enrichment in antiapoptotic B-cell leukemia/lymphoma 2 family protein expression, increased calcium flux, and increased protein glycosylation in myotubes and muscle tissue upon hyperammonemia. Critical molecules in these pathways were validated experimentally. Human skeletal muscle from patients with cirrhosis displayed similar responses, establishing translational relevance. These data demonstrate complex molecular interactions during adaptive and maladaptive responses during the cellular stress response to hyperammonemia.

Effect of heat acclimation on metabolic adaptations induced by endurance training in soleus rat muscle.

Aerobic training leads to well-known systemic metabolic and muscular alterations. Heat acclimation may also increase mitochondrial muscle mass. We studied the effects of heat acclimation combined with endurance training on metabolic adaptations of skeletal muscle. Thirty-two rats were divided into four groups: control (C), trained (T), heat-acclimated (H), and trained with heat acclimation (H+T) for 6 weeks. Soleus muscle metabolism was studied, notably by the in situ measurement of mitochondrial respiration with pyruvate (Pyr) or palmitoyl-coenzyme A (PCoA), under phosphorylating conditions ( V˙max ) or not ( V˙0 ). Aerobic performance increased, and retroperitoneal fat mass decreased with training, independently of heat exposure (p < 0.001 and p < 0.001, respectively). Citrate synthase and hydroxyl-acyl-dehydrogenase activity increased with endurance training (p < 0.001 and p < 0.01, respectively), without any effect of heat acclimation. Training induced an increase of the V˙0 and V˙max for PCoA (p < .001 and p < .01, respectively), without interference with heat acclimation. The training-induced increase of V˙0 (p < 0.01) for pyruvate oxidation was limited when combined with heat acclimation (-23%, p < 0.01). Training and heat acclimation independently increased the V˙max for pyruvate (+60% p < 0.001 and +50% p = 0.01, respectively), without an additive effect of the combination. Heat acclimation doubled the training effect on muscle glycogen storage (p < 0.001). Heat acclimation did not improve mitochondrial adaptations induced by endurance training in the soleus muscle, possibly limiting the alteration of carbohydrate oxidation while not facilitating fatty-acid utilization. Furthermore, the increase in glycogen storage observed after HA combined with endurance training, without the improvement of pyruvate oxidation, appears to be a hypoxic metabolic phenotype.

Metabolic Remodeling in Skeletal Muscle Atrophy as a Therapeutic Target.

Skeletal muscle is a highly responsive tissue, able to remodel its size and metabolism in response to external demand. Muscle fibers can vary from fast glycolytic to slow oxidative, and their frequency in a specific muscle is tightly regulated by fiber maturation, innervation, or external causes. Atrophic conditions, including aging, amyotrophic lateral sclerosis, and cancer-induced cachexia, differ in the causative factors and molecular signaling leading to muscle wasting; nevertheless, all of these conditions are characterized by metabolic remodeling, which contributes to the pathological progression of muscle atrophy. Here, we discuss how changes in muscle metabolism can be used as a therapeutic target and review the evidence in support of nutritional interventions and/or physical exercise as tools for counteracting muscle wasting in atrophic conditions.

Effects of Feeding Time on Markers of Muscle Metabolic Flexibility Following Acute Aerobic Exercise in Trained Mice Undergoing Time Restricted Feeding.

Time-restricted feeding (TRF) is becoming a popular way of eating in physically active populations, despite a lack of research on metabolic and performance outcomes as they relate to the timing of food consumption in relation to the time of exercise. The purpose of this study was to determine if the timing of feeding/fasting after exercise training differently affects muscle metabolic flexibility and response to an acute bout of exercise. Male C57BL/6 mice were randomized to one of three groups for 8 weeks. The control had ad libitum access to food before and after exercise training. TRF-immediate had immediate access to food for 6 h following exercise training and the TRF-delayed group had access to food 5-h post exercise for 6 h. The timing of fasting did not impact performance in a run to fatigue despite TRF groups having lower hindlimb muscle mass. TRF-delayed had lower levels of muscle HSL mRNA expression and lower levels of PGC-1α expression but displayed no changes in electron transport chain enzymes. These results suggest that in young populations consuming a healthy diet and exercising, the timing of fasting may not substantially impact metabolic flexibility and running performance.