Metabolic Capacity Of Skeletal Muscle Research Articles

Mustn1 ablation in skeletal muscle results in increased glucose tolerance concomitant with upregulated GLUT expression in male mice.

Glucose homeostasis is closely regulated to maintain energy requirements of vital organs and skeletal muscle plays a crucial role in this process. Mustn1 is expressed during embryonic and postnatal skeletal muscle development and its function has been implicated in myogenic differentiation and myofusion. Whether Mustn1 plays a role in glucose homeostasis in anyway remains largely unknown. As such, we deleted Mustn1 in skeletal muscle using a conditional knockout (KO) mouse approach. KO mice did not reveal any specific gross phenotypic alterations in skeletal muscle. However, intraperitoneal glucose tolerance testing (IPGTT) revealed that 2-month-old male KO mice had significantly lower glycemia than their littermate wild type (WT) controls. These findings coincided with mRNA changes in genes known to be involved in glucose metabolism, tolerance, and insulin sensitivity; 2-month-old male KO mice had significantly higher expression of GLUT1 and GLUT10 transporters, MUP-1 while OSTN expression was lower. These differences in glycemia and gene expression were statistically insignificant after 4 months. Identical experiments in female KO and WT control mice did not indicate any differences at any age. Our results suggest a link between Mustn1 expression and glucose homeostasis during a restricted period of skeletal muscle development/maturation. While this is an observational study, Mustn1's relationship to glucose homeostasis appears to be more complex with a possible connection to other key proteins such as GLUTs, MUP-1, and OSTN. Additionally, our data indicate temporal and sex differences. Lastly, our findings strengthen the notion that Mustn1 plays a role in the metabolic capacity of skeletal muscle.

Muscle PGC-1α modulates hepatic mitophagy regulation during aging

Aging has been suggested to be associated with changes in oxidative capacity, autophagy, and mitophagy in the liver, but a simultaneous evaluation of these key cellular processes is lacking. Moreover, skeletal muscle transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α has been reported to mediate inter-organ signaling through myokines with regulatory effects in the liver, but the potential role of muscle PGC-1α on hepatic changes with age remains to be resolved. The aim of the present study was therefore to investigate 1) the effect of aging on mitochondrial autophagy and mitophagy capacity in mouse liver and 2) whether muscle PGC-1α is required for maintaining autophagy and mitophagy capacity in the liver during aging. The liver was obtained from young (Young) and aged (Aged) inducible muscle-specific PGC-1α knockout (iMKO) and floxed littermate control mice (Lox). Aging increased liver p62, Parkin and BCL2/adenovirus E1B 19 kDa protein-interacting protein (BNIP)3 protein with no effect of muscle specific PGC-1α knockout, while liver Microtubule-associated protein 1A/1B-light chain 3(LC3) II/I was unchanged with age, but tended to be lower in iMKO mice than in controls. Markers of liver mitochondrial oxidative capacity and oxidative stress were unchanged with age and iMKO. However, Parkin protein levels in isolated liver mitochondria were 2-fold higher in Aged iMKO mice than in Aged controls. In conclusion, aging had no effect on oxidative capacity and lipid peroxidation in the liver. However, aging was associated with increased levels of autophagy and mitophagy markers. Moreover, muscle PGC-1α appears to regulate hepatic mitochondrial translocation of Parkin in aged mice, suggesting that the metabolic capacity of skeletal muscle can modulate mitophagy regulation in the liver during aging.

One Bout of Aerobic Exercise Elicits Alterations in The Expression of Mitochondrial Unfolded Protein Response (UPRmt) Markers in Skeletal Muscle

Muscle contractions during aerobic exercise stimulate molecular pathways to promote the production of new mitochondria, and improve their function. These adaptations translate into improved oxygen consumption and metabolic capacity of skeletal muscle. However, the increased drive for mitochondrial biogenesis during contractile activity causes an accumulation of misfolded proteins, disrupting mitochondrial homeostasis. The action of the UPRmt, a cytoprotective stress response pathway, is required to mitigate the associated proteotoxicity. This protein quality control mechanism favours the transcription of mitochondrial chaperones and proteases to refold and degrade the defective proteins, while inhibiting global protein translation. However, the regulation and activity of the UPRmt in helping skeletal muscle adapt to exercise stress during and after an acute bout of exercise has yet to be determined. Thus, to investigate this, mice were separated into sedentary (SED), acute exercise (AE) and acute exercise with recovery (AER) groups (n=4/group). The exercise consisted of 90-minutes of treadmill running at 15m/min. Tibialis anterior muscles were extracted from the AE groups immediately following exercise and from the AER group 3 hours post-exercise. Total RNA was isolated and mRNA levels were measured using qPCR. In line with previous data, PGC-1α mRNA increased by 50% in the AE group and increased further to 3.4-fold in the AER group. Activating transcription factor 5 (ATF5), an important regulator of UPRmt gene expression, did not change with acute exercise or recovery. ATF4, another transcription factor for stress-responsive genes, was also unchanged at the end of exercise, but was upregulated by 28% in the recovery period. mRNA levels of downstream targets of ATF5, Lon protease (LonP) and chaperones (HSP60 and GRP75) were upregulated by 18%, 24% and 77%, respectively. HSP60 mRNA returned to control levels during recovery, while GRP75 and LonP mRNAs remained elevated in the AER group. Our data indicate that acute exercise influences the expression of genes involved in both mitochondrial biogenesis and those of the UPRmt, contributing to the maintenance of organelle proteostasis in exercised muscle. Investigating the regulatory mechanisms governing this acute mitochondrial stress response is critical, as preservation of cellular function in the face of exercise-induced stress is essential for metabolic adaptations in muscle and thus, for whole-body homeostasis.

Epigenetics regulates gene expression patterns of skeletal muscle induced by physical exercise.

As it is well known, proper exercise benefits our mind and body, especially the skeletal muscle. Exercise increases the capacity of muscle metabolism, enhances the biological function of mitochondria, regulates the transformation of muscle fiber types and increases the muscle power. In recent years, more and more researches show that epigenetic regulation plays an important role in strengthening the muscle, and these studies mainly include DNA methylation, histone modification, and regulation of miRNA expression. In order to adapt to the body movement, these three epigenetic patterns change the metabolic capacity of skeletal muscle, mitochondrial biological function and muscle fiber types by regulating the gene expression of skeletal muscle. In this review, we summarize research progresses of exercise-induced epigenetic regulation of gene expression of skeletal muscle, in order to provide a reference for further studies of how sports improve our body health.

Does the thermal plasticity of metabolic enzymes underlie thermal compensation of locomotor performance in the eastern newt (Notophthalmus viridescens)?

Eastern newts (Notophthalmus viridescens) upregulate the metabolic capacity of skeletal muscle in winter to compensate for thermodynamic effects on metabolism. However, whether this compensation facilitates locomotor performance at low temperature is unknown. Therefore, our aim was to determine if thermal acclimation of metabolic enzymes in muscle benefits locomotion. Eastern newts from southern Ohio were acclimated to cold (5°C, 10:14 L:D) or warm (25°C, 14:10 L:D) conditions for 12 weeks. Following acclimation, we measured the locomotor performance (burst speed and time until exhaustion) and the activities of metabolic enzymes in skeletal muscle at 5-30°C. Creatine kinase (CK) activity in skeletal muscle was higher in cold compared to warm-acclimated newts, and cold-acclimated newts had a higher burst speed at low temperature compared to warm-acclimated newts. At low temperature, time until exhaustion was higher in cold compared to warm-acclimated newts, but the activities of citrate synthase (CS) and cytochrome c oxidase (CCO) in muscle were lower in cold compared to warm-acclimated newts. Together, these results demonstrate that eastern newts compensate for the effects of low temperature on locomotor performance. Whereas thermal compensation of CK activity is correlated with burst locomotion at low temperature, aerobic enzymes in skeletal muscle (CS and CCO) are not linked to compensation of sustained locomotion.

Exercise and MEF2–HDAC interactions

Exercise increases the metabolic capacity of skeletal muscle, which improves whole-body energy homeostasis and contributes to the positive health benefits of exercise. This is, in part, mediated by increases in the expression of a number of metabolic enzymes, regulated largely at the level of transcription. At a molecular level, many of these genes are regulated by the class II histone deacetylase (HDAC) family of transcriptional repressors, in particular HDAC5, through their interaction with myocyte enhancer factor 2 transcription factors. HDAC5 kinases, including 5'-AMP-activated protein kinase and protein kinase D, appear to regulate skeletal muscle metabolic gene transcription by inactivating HDAC5 and inducing HDAC5 nuclear export. These mechanisms appear to participate in exercise-induced gene expression and could be important for skeletal muscle adaptations to exercise.

Skeletal muscle, physical activity, and health

The skeletal muscle metabolic capacity plays a significant role for insulin sensitivity and the blood lipid profile. The metabolic capacity of the muscle is a function of the individual's physical activity level. This is also true for the content of type IIx muscle fibers, which is reduced, and the number of capillaries, which is elevated with muscle usage. Several of these skeletal muscle features are risk factors for, or linked with life style-induced diseases, such as type II diabetes, hypertension, hyperlipaemia, and obesity. This central role of the skeletal muscle and its functional metabolic capacity for life style diseases highlights the importance of maintaining daily physical activity. This article focuses on the link between the metabolic capacity of skeletal muscle and the metabolic syndrome and briefly discusses possible metabolic explanations for this relationship. The important aspect is that when the capacity of lipid oxidation is high in skeletal muscle, more saturated fatty acids are oxidized and more unsaturated fatty acids are built into the phospholipid fraction of the plasma membrane, giving it more fluidity and improved insulin sensitivity. Moreover, the article points to the role of these fatty acids in activating genes via the PPAR-receptor system essential for enzyme and transport proteins in the lipid metabolism.

The effects of aging on enzyme activities and metabolite concentrations in skeletal muscle from sedentary male and female subjects.

Aging affects the metabolic capacity of skeletal muscle, in particular the glycolytic and respiratory capacities. The purpose of this study was to quantify biochemical alterations due to aging in muscular metabolic capacity in human skeletal muscles in sedentary subjects. The activities of various marker enzymes and metabolites related to glycolysis, Krebs' cycle and the electron transfer chain and high energy phosphate compounds were measured in muscle biopsies from the rectus abdominis, vastus lateralis, and gluteus maximus muscles of 76 sedentary subjects (32 males and 44 females) between 15 and 91 yr. No significant differences between males and females were found, but changes related to age were: a decrease in hexokinase and lactate dehydrogenase activities in the rectus abdominis; a decrease in citrate synthase activity and citrate in the vastus lateralis; an increase in pyruvate kinase activity and a decrease in ATP and creatine phosphate concentrations in the gluteus maximus. These data suggest that distinct muscles may respond differently to aging regardless of sex in sedentary subjects.

Markers of capacity to utilize fatty acids in human skeletal muscle: relation to insulin resistance and obesity and effects of weight loss.

A number of biochemical defects have been identified in glucose metabolism within skeletal muscle in obesity, and positive effects of weight loss on insulin resistance are also well established. Less is known about the capacity of skeletal muscle for the metabolism of fatty acids in obesity-related insulin resistance and of the effects of weight loss, though it is evident that muscle contains increased triglyceride. The current study was therefore undertaken to profile markers of human skeletal muscle for fatty acid metabolism in relation to obesity, in relation to the phenotype of insulin-resistant glucose metabolism, and to examine the effects of weight loss. Fifty-five men and women, lean and obese, with normal glucose tolerance underwent percutaneous biopsy of vastus lateralis skeletal muscle for determination of HADH, CPT, heparin-releasable (Hr) and tissue-extractable (Ext) LPL, CS, COX, PFK, and GAPDH enzyme activities, and content of cytosolic and plasma membrane FABP. Insulin sensitivity was measured using the euglycemic clamp method. DEXA was used to measure FM and FFM. In skeletal muscle of obese individuals, CPT, CS, and COX activities were lower while, conversely, they had a higher or similar content of FABP(C) and FABP(PM) than in lean individuals. Hr and Ext LPL activities were similar in both groups. In multivariate and simple regression analyses, there were significant correlations between insulin resistance and several markers of FA metabolism, notably, CPT and FABP(PM). These data suggest that in obesity-related insulin resistance, the metabolic capacity of skeletal muscle appears to be organized toward fat esterification rather than oxidation and that dietary-induced weight loss does not correct this disposition.

Energy metabolism of skeletal muscle biopsies stimulated anaerobically without load in vitro.

This study was made to test the validity of a simple biopsy technique for assessing the metabolic capacity of skeletal muscle. The biopsy is stimulated under mineral oil without attachment, i.e., without load or tension, then freeze-clamped and assayed for ATP, phosphocreatine, glucose 6-phosphate, and lactate. The mineral oil creates a closed anaerobic system. Background studies demonstrated in the absence of a load, metabolic changes with stimulation were little affected by cutting the fibers to obtain the biopsy; and high-energy phosphate (approximately P) consumption during a brief tetanus was not much lower than that for an isometric tetanus. Individual fast-twitch oxidative-glycolytic (IIA) and fast-twitch glycolytic (IIB) fibers obtained from the freeze-clamped biopsy showed distinct differences in approximately P consumption and metabolic changes. The results indicate that this technique could be useful for studies of normal and pathological human muscle.

Malleability of the system in overcoming limitations: functional elements.

Three different views can be found in the literature concerning the classical question in exercise physiology: what limits maximal oxygen uptake in man? Some authors believe that the limitation is the maximal rate of oxygen delivery by the cardiovascular system. Others argue that oxygen uptake is limited by the capillary bed or metabolic capacity of skeletal muscle, and the third line of thought is that no single factor can be found to be directly limiting as all links in the oxygen transport are so closely matched. The stand taken in this paper is that the skeletal muscle of man can be excluded as a limiting factor for maximal oxygen uptake in whole body exercise. It can be shown, by direct measurements, that in sedentary and in trained man maximal perfusion and oxygen utilization of skeletal muscle is so high that if all muscles in the body were engaged in intense exercise, the cardiac pump function would have to be 2-3 fold larger than it is. What happens in whole body exercise is that each muscle group receives only a fraction of the blood it can accommodate. The primary role for a larger capillary network observed in trained muscles is to keep or extend mean transit time. Elevated mitochondrial enzyme activities affect the metabolic response (i.e. lipid oxidation is elevated in trained muscles). However, these adaptations are not necessary for increasing the maximal oxygen uptake of man, as the capacity of the heart is limiting. Improved training techniques (which induce even larger improvements in cardiac pump function) may reveal that pulmonary diffusion capacity is the limiting factor.