Skeletal Muscle Energy Metabolism Research Articles

Diabetes Pharmacotherapy and its effects on the Skeletal Muscle Energy Metabolism.

The disorders of skeletal muscle metabolism in patients with Type 2 diabetes mellitus (T2DM), such as mitochondrial defection and glucose transporters (GLUTs) translocation dysfunctions, are not uncommon. Therefore, when anti-diabetic drugs were used in various chronic diseases associated with hyperglycemia, the impact on skeletal muscle should not be ignored. However, current studies mainly focus on muscle mass rather than metabolism or functions. Anti-diabetic drugs might have a harmful or beneficial impact on skeletal muscle. In this review, we summarize the upto- date studies on the effects of anti-diabetic drugs and some natural compounds on skeletal muscle metabolism, focusing primarily on emerging data from pre-clinical to clinical studies. Given the extensive use of anti-diabetic drugs and the common sarcopenia, a better understanding of energy metabolism in skeletal muscle deserves attention in future studies.

Low serum brain-derived neurotrophic factor may predict poor response to cardiac rehabilitation in patients with cardiovascular disease.

It has been shown that serum brain-derived neurotrophic factor (BDNF) is associated with skeletal muscle energy metabolism and that BDNF is a predictor of mortality in heart failure patients. However, little is known about the relationship between BDNF and cardiac rehabilitation (CR). Therefore, this study retrospectively investigated the effects of baseline serum BDNF levels on the CR-induced exercise capacity improvement in patients with cardiovascular disease (CVD). We assigned 99 CVD patients (mean age 71±12 years, male = 60) to Low, Middle, and High groups based on the tertiles of baseline BDNF levels. Cardiopulmonary exercise testing was done using supervised bicycle ergometer twice before and after 3 weeks of CR. Analysis of covariance (ANCOVA) followed by post-hoc analysis using Tukey's HSD test was conducted to assess the multivariate associations between baseline BDNF levels categorized by BDNF tertiles (as independent variable) and %increases in AT and peak VO2 after 3-week CR (as dependent variables) after adjustment for age and gender (as covariates), as a main statistical analysis of the present study. The higher the baseline BDNF levels, the better nutritional status evaluated by the CONUT score (p<0.0001). Baseline anaerobic threshold (AT) and peak oxygen uptake (peak VO2) were similar among the three groups. ANCOVA followed by post-hoc analysis revealed that age- and gender-adjusted %increases in peak VO2 after 3-week CR were positively associated with baseline BDNF levels (p = 0.0239) and Low BDNF group showed significantly lower %increase in peak VO2 than High BDNF group (p = 0.0197). Significant association was not found between baseline BDNF and %increase in AT (p = 0.1379). Low baseline BDNF levels were associated with malnutrition in CVD patients. A positive association between baseline BDNF levels and CR-induced increases in peak VO2 was found. It was suggested that CVD patients with low baseline BDNF levels may be poor responders to CR.

17β-Estradiol Effects in Skeletal Muscle: A 31P MR Spectroscopic Imaging (MRSI) Study of Young Females during Early Follicular (EF) and Peri-Ovulation (PO) Phases

The natural variation in estrogen secretion throughout the female menstrual cycle impacts various organs, including estrogen receptor (ER)-expressed skeletal muscle. Many women commonly experience increased fatigue or reduced energy levels in the days leading up to and during menstruation, when blood estrogen levels decline. Yet, it remains unclear whether endogenous 17β-estradiol, a major estrogen component, directly affects the energy metabolism in skeletal muscle due to the intricate and fluctuating nature of female hormones. In this study, we employed 2D 31P FID-MRSI at 7T to investigate phosphoryl metabolites in the soleus muscle of a cohort of young females (average age: 28 ± 6 years, n = 7) during the early follicular (EF) and peri-ovulation (PO) phases, when their blood 17β-estradiol levels differ significantly (EF: 28 ± 18 pg/mL vs. PO: 71 ± 30 pg/mL, p &lt; 0.05), while the levels of other potentially interfering hormones remain relatively invariant. Our findings reveal a reduction in ATP-referenced phosphocreatine (PCr) levels in the EF phase compared to the PO phase for all participants (5.4 ± 4.3%). Furthermore, we observe a linear correlation between muscle PCr levels and blood 17β-estradiol concentrations (r = 0.64, p = 0.014). Conversely, inorganic phosphate Pi and phospholipid metabolite GPC levels remain independent of 17β-estradiol but display a high correlation between the EF and PO phases (p = 0.015 for Pi and p = 0.0008 for GPC). The robust association we have identified between ATP-referenced PCr and 17β-estradiol suggests that 17β-estradiol plays a modulatory role in the energy metabolism of skeletal muscle.

The role of estrogen in female skeletal muscle aging: A systematic review.

Aging is associated with a loss of skeletal muscle mass and function that negatively impacts the independence and quality of life of older individuals. Females demonstrate a distinct pattern of muscle aging compared to males, potentially due to menopause, when the production of endogenous sex hormones declines. This systematic review aims to investigate the current knowledge about the role of estrogen in female skeletal muscle aging. A systematic search of MEDLINE Complete, Global Health, Embase, PubMed, SPORTDiscus, and CINHAL was conducted. Studies were considered eligible if they compared a state of estrogen deficiency (e.g. postmenopausal females) or supplementation (e.g. estrogen therapy) to normal estrogen conditions (e.g. premenopausal females or no supplementation). Outcome variables of interest included measures of skeletal muscle mass, function, damage/repair, and energy metabolism. Quality assessment was completed with the relevant Johanna Briggs critical appraisal tool, and data were synthesized in a narrative manner. Thirty-two studies were included in the review. Compared to premenopausal women, postmenopausal women had reduced muscle mass and strength, but the effect of menopause on markers of muscle damage and expression of the genes involved in metabolic signaling pathways remains unclear. Some studies suggest a beneficial effect of estrogen therapy on muscle size and strength, but evidence is largely conflicting and inconclusive, potentially due to large variations in the reporting and status of exposure and outcomes. The findings from this review point toward a potential negative effect of estrogen deficiency on aging skeletal muscle, but further mechanistic evidence is needed to clarify its role.

Intravenous iron supplementation improves energy metabolism of exercising skeletal muscles without effect on either oxidative stress or inflammation in male patients with heart failure with reduced ejection fraction.

Skeletal muscle dysfunction is a feature of heart failure (HF). Iron deficiency (ID) is prevalent in patients with HF associated with exercise intolerance and poor quality of life. Intravenous iron in iron deficient patients with HF has attenuated HF symptoms, however the pathomechanisms remain unclear. The aim of study was to assess whether intravenous iron supplementation as compared to placebo improves energy metabolism of skeletal muscles in patients with HF. Men with heart failure with reduced ejection fraction (HFrEF) and ID were randomised in 1:1 ratio to either intravenous ferric carboxymaltose (IV FCM) or placebo. In vivo reduction of lactates by exercising skeletal muscles of forearm was analyzed. A change in lactate production between week 0 and 24 was considered as a primary endpoint of the study. There were two study arms: the placebo and the IV FCM (12 and 11 male patients with HFrEF). At baseline, there were no differences between these two study arms. IV FCM therapy as compared to placebo reduced the exertional production of lactates in exercising skeletal muscles. These effects were accompanied by a significant increase in both serum ferritin and transferrin saturation in the IV FCM arm which was not demonstrated in the placebo arm. Intravenous iron supplementation in iron deficient men with HFrEF improves the functioning of skeletal muscles via an improvement in energy metabolism in exercising skeletal muscles, limiting the contribution of anaerobic reactions generating ATP as reflected by a lower in vivo lactate production in exercising muscles in patients with repleted iron stores.

Maximal oxidative capacity during exercise is associated with muscle power output in patients with long coronavirus disease 2019 (COVID-19) syndrome. A moderation analysis

Long COVID syndrome (LCS) involves persistent symptoms experienced by many patients after recovering from coronavirus disease 2019 (COVID-19). We aimed to assess skeletal muscle energy metabolism, which is closely related to substrate oxidation rates during exercise, in patients with LCS compared with healthy controls. We also examined whether muscle power output mediates the relationship between COVID-19 and skeletal muscle energy metabolism. In this cross-sectional study, we enrolled 71 patients with LCS and 63 healthy controls. We assessed clinical characteristics such as body composition, physical activity, and muscle strength. We used cardiopulmonary exercise testing to evaluate substrate oxidation rates during graded exercise. We performed statistical analyses to compare group characteristics and peak fat oxidation differences based on power output. The two-way analysis of covariance (ANCOVA) results, adjusted for covariates, showed that the patients with LCS had lower absolute maximal fatty acid oxidation (MFO), relative MFO/fat free mass (FFM), absolute carbohydrates oxidation (CHox), relative CHox/FFM, and oxygen uptake (V˙˙O2) at maximum fat oxidation (g min-1) than the healthy controls (P<0.05). Moderation analysis indicated that muscle power output significantly influenced the relationship between LCS and reduced peak fat oxidation (interaction β=-0.105 [95% confidence interval-0.174;-0.036]; P=0.026). Therefore, when muscle power output was below 388W, the effect of the LCS on MFO was significant (62% in our study sample P=0.010). These findings suggest compromised mitochondrial bioenergetics and muscle function, represented by lower peak fat oxidation rates, in the patients with LCS compared with the healthy controls. The patients with LCS had lower peak fat oxidation during exercise compared with the healthy controls, potentially indicating impairment in skeletal muscle function. The relationship between peak fat oxidation and LCS appears to be mediated predominantly by muscle power output. Additional research should continue investigating LCS pathogenesis and the functional role of mitochondria.

Alteration of skeletal muscle energy metabolism assessed by phosphorus-31 magnetic resonance spectroscopy in clinical routine, part 1: Advanced quality control pipeline.

Implementing a standardized phosphorus-31 magnetic resonance spectroscopy (31 P-MRS) dynamic acquisition protocol to evaluate skeletal muscle energy metabolism and monitor muscle fatigability, while being compatible with various longitudinal clinical studies on diversified patient cohorts, requires a high level of technicality and expertise. Furthermore, processing data to obtain reliable results also demands a great degree of expertise from the operator. In this two-part article, we present an advanced quality control approach for data acquired using a dynamic 31 P-MRS protocol. The aim is to provide decision support to the operator to assist in data processing and obtain reliable results based on objective criteria. We present here, in part 1, an advanced data quality control (QC) approach of a dynamic 31 P-MRS protocol. Part 2 is an impact study that will demonstrate the added value of the QC approach to explore data derived from two clinical populations that experience significant fatigue, patients with coronavirus disease 2019 and multiple sclerosis. In part 1, 31 P-MRS was performed using 3-T clinical MRI in 175 subjects from clinical and healthy control populations conducted in a University Hospital. An advanced data QC score (QCS) was developed using multiple objective criteria. The criteria were based on current recommendations from the literature enriched by new proposals based on clinical experience. The QCS was designed to indicate valid and corrupt data and guide necessary objective data editing to extract as much valid physiological data as possible. Dynamic acquisitions using an MR-compatible ergometer ran over a rest (40 s), exercise (2 min), and a recovery phase (6 min). Using QCS enabled rapid identification of subjects with data anomalies, allowing the user to correct the data series or reject them partially or entirely, as well as identify fully valid datasets. Overall, the use of the QCS resulted in the automatic classification of 45% of the subjects, including 58 participants who had data with no criterion violation and 21 participants with violations that resulted in the rejection of all dynamic data. The remaining datasets were inspected manually with guidance, allowing acceptance of full datasets from an additional 80 participants and recovery phase data from an additional 16 subjects. Overall, more anomalies occurred with patient data (35% of datasets) compared with healthy controls (15% of datasets). In conclusion, the QCS ensures a standardized data rejection procedure and rigorous objective analysis of dynamic 31 P-MRS data obtained from patients. This methodology contributes to efforts made to standardize 31 P-MRS practices that have been underway for a decade, with the goal of making it an empowered tool for clinical research.

Alteration of skeletal muscle energy metabolism assessed by 31 P MRS in clinical routine: Part 2. Clinical application.

In this second part of a two-part paper, we intend to demonstrate the impact of the previously proposed advanced quality control pipeline. To understand its benefit and challenge the proposed methodology in a real scenario, we chose to compare the outcome when applying it to the analysis of two patient populations with significant but highly different types of fatigue: COVID-19 and multiple sclerosis (MS). 31 P-MRS was performed on a 3 T clinical MRI, in 19 COVID-19 patients, 38 MS patients, and 40 matched healthy controls. Dynamic acquisitions using an MR-compatible ergometer ran over a rest (40 s), exercise (2 min), and a recovery phase (6 min). Long and short TR acquisitions were also made at rest for T1 correction. The advanced data quality control pipeline presented in Part 1 is applied to the selected patient cohorts to investigate its impact on clinical outcomes. We first used power and sample size analysis to estimate objectively the impact of adding the quality control score (QCS). Then, comparisons between patients and healthy control groups using the validated QCS were performed using unpaired t tests or Mann-Whitney tests (p < 0.05). The application of the QCS resulted in increased statistical power, changed the values of several outcome measures, and reduced variability (standard deviation). A significant difference was found between the T1PCr and T1Pi values of MS patients and healthy controls. Furthermore, the use of a fixed correction factor led to systematically higher estimated concentrations of PCr and Pi than when using individually corrected factors. We observed significant differences between the two patient populations and healthy controls for resting [PCr]-MS only, [Pi ], [ADP], [H2 PO4 - ], and pH-COVID-19 only, and post-exercise [PCr], [Pi ], and [H2 PO4 - ]-MS only. The dynamic indicators τPCr , τPi , ViPCr , and Vmax were reduced for COVID-19 and MS patients compared with controls. Our results show that QCS in dynamic 31 P-MRS studies results in smaller data variability and therefore impacts study sample size and power. Although QCS resulted in discarded data and therefore reduced the acceptable data and subject numbers, this rigorous and unbiased approach allowed for proper assessment of muscle metabolites and metabolism in patient populations. The outcomes include an increased metabolite T1 , which directly affects the T1 correction factor applied to the amplitudes of the metabolite, and a prolonged τPCr , indicating reduced muscle oxidative capacity for patients with MS and COVID-19.

Selection and evaluation of biomarkers of Gynostemma pentaphyllum (Thunb.) Makino representing its tonifying weakness and strengthening muscle effect based on PXR/IL-6/SERCA1a regulation

TCM internal medication is usually beneficial after muscle injury or pulling, among which Gynostemma pentaphyllum (Thunb.) Makino (Gyp) has shown good activity; however, an explanation and evaluation of its therapeutic effect is needed. The problem lies in the fact that the main regulatory pathway for Gyp is unclear, lacking scientific and systematic mechanisms and standards. It was reported in our previous paper that components in Gyp regulate the expression of the PXR/IL-6/SERCA1a signaling pathway to achieve such therapy, but there remains a lack of an accurate method and standard for evaluation. In this study, based on our previous discovery, a relatively comprehensive and accurate investigation was carried out to establish the metabolomic profile of Gyp’s therapeutic effect, Metabolomics studies showed that a total of 49 different metabolites were found, of which 24 were related to PXR-IL-6-SERCA1a, and they were mainly involved in skeletal muscle cell repair, material and energy metabolism, and inflammatory response, which not only provides accurate standards for PXR/IL-6/SERCA1a regulation but also explains its tonifying weakness and strengthening muscle effect in TCM theory in a scientific and quantitative way.

Classification of Exergames with Different Types: Perceptual and Physiological Responses in College Students

This study aimed to (i) investigate and compare the effects of five different types of active video games (AVGs) on physiological and perceptual variables, (ii) categorize the AVGs’ physical activity (PA) intensity according to ACSM classification, and (iii) investigate the correlation between rating of perceived exertion (RPE) and enjoyment score within each AVG. Twelve college students participated in this study. Each AVG was played randomly for 15 min on non-consecutive days. The physiological variables were measured with a breath-by-breath system continuously during the AVGs and resting conditions. The AVGs significantly increased oxygen consumption, respiratory exchange ratio, energy expenditure, metabolic equivalent, and heart rate compared to rest conditions (p &lt; 0.001). According to ACSM criteria, Fruit Ninja, Just Dance, and Shape-Up Muscle games were defined as moderate PA (MET = 4.07, 5.46, and 5.25; RPE = 10.33, 10.42, and 14.67 respectively) and Shape-Up Cardio, and Fighter Within games were defined as vigorous PA (MET = 6.83, and 7.03; RPE = 13.92, and 13.75 respectively). All games were enjoyable (&gt;27). Young adults can get the recommended PA intensity with AVGs, burning 80–150 kcal in 15 min. The findings suggest that energy expenditure may be similar among different types of AVGs. However, skeletal muscle energy metabolism may differ according to the type of AVG.

Nutritional regulation of skeletal muscle energy metabolism, lipid accumulation and meat quality in pigs.

The quality of pork determines consumers' purchase intention, which directly affects the economic value of pork. Minimizing the proportion of inferior pork and producing high quality pork are the ultimate goals of the pig industry. Muscle energy metabolism, serving as a regulative hub in organism energy expenditure and storage as a fat deposit, is compatible with myofiber type composition, affecting meat color, intramuscular fat content, tenderness, pH values and drip loss. Increasing data illustrate that dietary nutrients and bioactive ingredients affect muscle energy metabolism, white adipose browning and fat distribution, and myofiber type composition in humans, and rodents. Recently, some studies have shown that modulating muscle energy metabolism and lipid accumulation through nutritional approaches could effectively improve meat quality. This article reviews the progress and development in this field, and specifically discusses the impacts of dietary supply of amino acids, lipids, and gut microbiota as well as maternal nutrition on skeletal muscle energy metabolism, lipid accumulation and meat quality of pigs, so as to provide comprehensive overview with respect to effective avenues for improving meat quality.

Clock genes regulate skeletal muscle energy metabolism through NAMPT/NAD+/SIRT1 following heavy-load exercise.

The biological clock is an invisible "clock" in the organism, which can regulate behavior, physiology, and biochemical reactions. However, the relationship between clock genes and energy metabolism in postexercise skeletal muscle is not well known. The purpose of this study was to determine the mechanisms through which peripheral clock genes regulate energy metabolism in skeletal muscle. We analyzed the rhythm of mRNA expression of the clock genes Bmal1 and Clock in skeletal muscle following heavy-load exercise and measured related indicators of mitochondrial structure and function. We obtained the following experimental results. First, heavy-load exercise induced loss of circadian rhythm of Bmal1 between ZT0 and ZT24, and the circadian rhythm of Clock was not restored between ZT0 and ZT72. Second, analysis of mitochondrial morphology in group E showed abnormal swelling and ridge structure damage at ZT0, which recovered somewhat at ZT24 and ZT48, and the damage had essentially disappeared by ZT72. Third, the expression of NAMPT/NAD+/SIRT1 signaling axis proteins in group E was abnormal at ZT0, the content of NAMPT and the activity of SIRT1 significantly increased, and the content of NAD+ significantly decreased. Fourth, the expression of BMAL1 and PGC-1α in group E significantly increased, whereas the ATP and ADP content, as well as the activities of COXII and COXIV, were significantly changed. Finally, the colocalization of BMAL1 and SIRT1 in group E was significantly upregulated at ZT0. These results suggest that the skeletal muscle clock gene Bmal1 may regulate the energy metabolism level of skeletal muscle after exercise through the NAMPT/NAD+/SIRT1 signaling pathway.

Baf155 regulates skeletal muscle metabolism via HIF-1a signaling.

During exercise, skeletal muscle is exposed to a low oxygen condition, hypoxia. Under hypoxia, the transcription factor hypoxia-inducible factor-1α (HIF-1α) is stabilized and induces expressions of its target genes regulating glycolytic metabolism. Here, using a skeletal muscle-specific gene ablation mouse model, we show that Brg1/Brm-associated factor 155 (Baf155), a core subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, is essential for HIF-1α signaling in skeletal muscle. Muscle-specific ablation of Baf155 increases oxidative metabolism by reducing HIF-1α function, which accompanies the decreased lactate production during exercise. Furthermore, the augmented oxidation leads to high intramuscular adenosine triphosphate (ATP) level and results in the enhancement of endurance exercise capacity. Mechanistically, our chromatin immunoprecipitation (ChIP) analysis reveals that Baf155 modulates DNA-binding activity of HIF-1α to the promoters of its target genes. In addition, for this regulatory function, Baf155 requires a phospho-signal transducer and activator of transcription 3 (pSTAT3), which forms a coactivator complex with HIF-1α, to activate HIF-1α signaling. Our findings reveal the crucial role of Baf155 in energy metabolism of skeletal muscle and the interaction between Baf155 and hypoxia signaling.

Cysteine-cysteine Chemokine Receptor Type 5 Plays a Critical Role in Exercise Performance by Regulating Mitochondrial Content in Skeletal Muscle.

Cysteine-cysteine chemokine receptor type 5 (CCR5) is thought to play an important role in the trafficking of lymphoid cells but has recently also been associated with AMPK signaling pathways that are implicated in energy metabolism in skeletal muscle. We hypothesized that genetic deletions of CCR5 would alter mitochondria content and exercise performance in mice. CCR5-/- and wild-type mice with the same genetic background were subjected to endurance exercise and grip strength tests. The soleus muscle was stained with immunofluorescence for myosin heavy chain 7 (MYH7) and succinate dehydrogenase (SDH) analysis as well as the expression of genes associated with muscle atrophy and mitochondrial oxidative phosphorylation were measured using qPCR. Although there were no differences in the weight of the soleus muscle between the CCR5-/- group and the wild-type mice, the CCR5-/- mice showed the following muscular dysfunctions: (i) decreased MYH7 percentage and cross-section area, (ii) higher myostatin and atrogin-1 mRNA levels, (iii) dropped expression of mitochondrial DNA-encoded electron respiratory chain genes (cytochrome B, cytochrome c oxidase subunit III, and ATP synthase subunit 6) as well as mitochondrial generation genes (PPARγandPGC-1α), and (iv) lower SDH activity and exercise performance when compared with wild-type mice. In addition, genes associated with mitochondrial biogenesis (PGC-1α, PPARγ, and MFN2) and mitochondrial complex (ND4 and Cytb) were upregulated when the skeletal muscle cell line C2C12 was exposed to cysteine-cysteine chemokine ligand 4 (a ligand of CCR5) in vitro. These findings suggested that attenuation of endurance exercise performance is related to the loss of mitochondrial content and lower SDH activity of soleus muscle in CCR5 knockout mice. The present study provides evidence indicating that the chemokine receptor CCR5 might modulate the skeletal muscle metabolic energy system during exercise.

Association of carnitine insufficiency with sarcopenia and dynapenia in patients with heart failure.

L-carnitine transports fatty acids into mitochondria and contributes to energy metabolism in skeletal muscles. However, the association between carnitine insufficiency and skeletal muscle weakness, namely sarcopenia and dynapenia, in patients with heart failure (HF) remains unclear. In total, 124 patients with HF were enrolled in this study. Carnitine insufficiency was indicated by a decrease in serum free carnitine (FC) levels of less than 36 μmol/L or an elevated serum acylcarnitine (AC) to free carnitine (FC) ratio (AC/FC ratio) of 0.27 or higher. Skeletal muscle weakness was defined as reduced handgrip strength and classified into two phenotypes: sarcopenia (low muscle strength with low skeletal muscle mass) and dynapenia (low muscle strength with normal skeletal muscle mass). Patients with carnitine insufficiency had a significantly higher prevalence of muscle weakness and a lower 6-min walk distance than those without carnitine insufficiency (P < 0.05). A machine learning model showed that older age (≥77 years) and, in patients aged 64-76 years, a higher AC/FC ratio (≥0.31) were associated with sarcopenia. However, there was only a week association between carnitine levels and dynapenia. The effect of carnitine insufficiency on skeletal muscle weakness was greater in patients with low skeletal muscle mass than in those with normal skeletal muscle mass (P < 0.05 for interaction). Carnitine insufficiency is more closely associated with sarcopenia than with dynapenia in patients with HF, suggesting carnitine insufficiency as a potential therapeutic target for sarcopenia in these patients. Geriatr Gerontol Int 2023; 23: 524-530.

Skeletal Muscle-Specific Bis Depletion Leads to Muscle Dysfunction and Early Death Accompanied by Impairment in Protein Quality Control.

Bcl-2-interacting cell death suppressor (BIS), also called BAG3, plays a role in physiological functions such as anti-apoptosis, cell proliferation, autophagy, and senescence. Whole-body Bis-knockout (KO) mice exhibit early lethality accompanied by abnormalities in cardiac and skeletal muscles, suggesting the critical role of BIS in these muscles. In this study, we generated skeletal muscle-specific Bis-knockout (Bis-SMKO) mice for the first time. Bis-SMKO mice exhibit growth retardation, kyphosis, a lack of peripheral fat, and respiratory failure, ultimately leading to early death. Regenerating fibers and increased intensity in cleaved PARP1 immunostaining were observed in the diaphragm of Bis-SMKO mice, indicating considerable muscle degeneration. Through electron microscopy analysis, we observed myofibrillar disruption, degenerated mitochondria, and autophagic vacuoles in the Bis-SMKO diaphragm. Specifically, autophagy was impaired, and heat shock proteins (HSPs), such as HSPB5 and HSP70, and z-disk proteins, including filamin C and desmin, accumulated in Bis-SMKO skeletal muscles. We also found metabolic impairments, including decreased ATP levels and lactate dehydrogenase (LDH) and creatine kinase (CK) activities in the diaphragm of Bis-SMKO mice. Our findings highlight that BIS is critical for protein homeostasis and energy metabolism in skeletal muscles, suggesting that Bis-SMKO mice could be used as a therapeutic strategy for myopathies and to elucidate the molecular function of BIS in skeletal muscle physiology.

A Pilot Study of Ratiometric Creatine CEST MRI Assessment of Rabbit Skeletal Muscle Energy Metabolism at 3 T.

pH MRI may provide useful information to evaluate metabolic disruption following ischemia. Radiofrequency amplitude-based creatine chemical exchange saturation transfer (CrCEST) ratiometric MRI is pH-sensitive, which could but has not been explored to examine muscle ischemia. To investigate skeletal muscle energy metabolism alterations with CrCEST ratiometric MRI. Prospective. Seven adult New Zealand rabbits with ipsilateral hindlimb muscle ischemia. 3 T/two MRI scans, including MRA and CEST imaging, were performed under two B1 amplitudes of 0.5 and 1.25 μT after 2 hours of hindlimb muscle ischemia and 1 hour of reperfusion recovery, respectively. CEST effects of two energy metabolites of creatine and phosphocreatine (PCrCEST) were resolved with the multipool Lorentzian fitting approach. The pixel-wise CrCEST ratio was quantified by calculating the ratio of the resolved CrCEST peaks under a B1 amplitude of 1.25 μT to those under 0.5 μT in the entire muscle. One-way ANOVA and Pearson's correlation. P < 0.05 was considered statistically significant. MRA images confirmed the blood flow loss and restoration in the ischemic hindlimb at the ischemia and recovery phases, respectively. Ischemic muscles exhibited a significant decrease of PCr at the ischemia (under both B1 amplitudes) and recovery phases (under B1 amplitude of 0.5 μT) and significantly increased CrCEST from normal tissues at both phases (under both B1 levels). Specifically, CrCEST decreased, and PCrCEST increased with the CrCEST ratio. Significantly strong correlations were observed among the CrCEST ratio, and CrCEST and PCrCEST under both B1 levels (r > 0.80). The CrCEST ratio altered substantially with muscle pathological states and was closely related to CEST effects of energy metabolites of Cr and PCr, suggesting that the pH-sensitive CrCEST ratiometric MRI is feasible to evaluate muscle injuries at the metabolic level. 2 TECHNICAL EFFICACY STAGE: 1.

RIP140 deficiency enhances cardiac fuel metabolism and protects mice from heart failure.

During the development of heart failure (HF), the capacity for cardiomyocyte (CM) fatty acid oxidation (FAO) and ATP production is progressively diminished, contributing to pathologic cardiac hypertrophy and contractile dysfunction. Receptor-interacting protein 140 (RIP140, encoded by Nrip1) has been shown to function as a transcriptional corepressor of oxidative metabolism. We found that mice with striated muscle deficiency of RIP140 (strNrip1-/-) exhibited increased expression of a broad array of genes involved in mitochondrial energy metabolism and contractile function in heart and skeletal muscle. strNrip1-/- mice were resistant to the development of pressure overload-induced cardiac hypertrophy, and CM-specific RIP140-deficient (csNrip1-/-) mice were protected against the development of HF caused by pressure overload combined with myocardial infarction. Genomic enhancers activated by RIP140 deficiency in CMs were enriched in binding motifs for transcriptional regulators of mitochondrial function (estrogen-related receptor) and cardiac contractile proteins (myocyte enhancer factor 2). Consistent with a role in the control of cardiac fatty acid oxidation, loss of RIP140 in heart resulted in augmented triacylglyceride turnover and fatty acid utilization. We conclude that RIP140 functions as a suppressor of a transcriptional regulatory network that controls cardiac fuel metabolism and contractile function, representing a potential therapeutic target for the treatment of HF.

Development of three-dimensional primary human myospheres as culture model of skeletal muscle cells for metabolic studies.

Introduction: Skeletal muscle is a major contributor to whole-body energy homeostasis and the utilization of fatty acids and glucose. At present, 2D cell models have been the most used cellular models to study skeletal muscle energy metabolism. However, the transferability of the results to in vivo might be limited. This project aimed to develop and characterize a skeletal muscle 3D cell model (myospheres) as an easy and low-cost tool to study molecular mechanisms of energy metabolism. Methods and results: We demonstrated that human primary myoblasts form myospheres without external matrix support and carry structural and molecular characteristics of mature skeletal muscle after 10days of differentiation. We found significant metabolic differences between the 2D myotubes model and myospheres. In particular, myospheres showed increased lipid oxidative metabolism than the 2D myotubes model, which oxidized relatively more glucose and accumulated more oleic acid. Discussion and conclusion: These analyses demonstrate model differences that can have an impact and should be taken into consideration for studying energy metabolism and metabolic disorders in skeletal muscle.

Insulin, dibutyryl-cAMP, and glucose modulate expression of patatin-like domain containing protein 7 in cultured human myotubes.

Expression of patatin-like phospholipase domain containing protein 7 (PNPLA7), also known as neuropathy target esterase-related esterase (NRE), a lysophospholipase, increases with fasting and decreases with feeding in mouse skeletal muscle, indicating it is regulated by insulin, counterregulatory hormones, such as glucocorticoids and catecholamines, and/or nutrients. In cultured mouse adipocytes insulin reduces Pnpla7 expression, underscoring the possibility that insulin regulates PNPLA7 in skeletal muscle. The first aim of this study was to establish whether PNPLA7 is functionally expressed in cultured human skeletal muscle cells. The second aim was to determine whether PNPLA7 is regulated by insulin, glucocorticoids, cAMP/protein kinase A pathway, and/or glucose. Cultured human skeletal muscle cells expressed PNPLA7 mRNA and protein. Gene silencing of PNPLA7 in myoblasts reduced the phosphorylation of 70 kDa ribosomal protein S6 kinase and ribosomal protein S6 as well as the abundance of α1-subunit of Na+,K+-ATPase and acetyl-CoA carboxylase, indirectly suggesting that PNPLA7 is functionally important. In myotubes, insulin suppressed PNPLA7 mRNA at 1 g/L glucose, but not at low (0.5 g/L) or high (4.5 g/L) concentrations. Treatment with synthetic glucocorticoid dexamethasone and activator of adenylyl cyclase forskolin had no effect on PNPLA7 regardless of glucose concentration, while dibutyryl-cAMP, a cell-permeable cAMP analogue, suppressed PNPLA7 mRNA at 4.5 g/L glucose. The abundance of PNPLA7 protein correlated inversely with the glucose concentrations. Collectively, our results highlight that PNPLA7 in human myotubes is regulated by metabolic signals, implicating a role for PNPLA7 in skeletal muscle energy metabolism.