Muscle Dysfunction Research Articles

Dynamic changes of diaphragm and limb skeletal muscle in patients with sepsis assessed by bedside ultrasound and their correlation with blood urea/creatinine ratio

To investigate the dynamic changes of diaphragm and limb skeletal muscle in patients with sepsis by bedside ultrasound and their correlation with the ratio of blood urea/creatinine ratio (UCR) in 7 days after intensive care unit (ICU) admission. A prospective observational study was conducted. A total of 55 patients with sepsis admitted to ICU of General Hospital of Ningxia Medical University from June 2022 to February 2023 were selected as the research objects. General information, laboratory indicators [urea, serum creatinine (SCr), and UCR] on days 1, 4, and 7 of ICU admission, and prognostic indicators were observed. Bedside ultrasound was used to assess the dynamic changes of diaphragm morphology [including diaphragmatic excursion (DE), end-inspiratory diaphragm thickness (DTei), and end-expiratory diaphragm thickness (DTee)] on days 1, 4, and 7 of ICU admission, as well as limb skeletal muscle (quadriceps femoris) morphology [including rectus femoris-muscle layer thickness (RF-MLT), vastus intermedius-muscle layer thickness (VI-MLT), and rectus femoris-cross sectional area (RF-CSA)]. Diaphragm thickening fraction (DTF) and RF-CSA atrophy rate were calculated, and the incidence of diaphragm and limb skeletal muscle dysfunction was recorded. The correlation between ultrasound morphological parameters of diaphragm and quadriceps and UCR at each time points in 7 days after ICU admission was analyzed by Pearson correlation. A total of 55 patients with sepsis were included, of which 29 were in septic shock. As the duration of ICU admission increased, the incidence of diaphragm dysfunction in patients with sepsis increased first and then decreased (63.6%, 69.6%, and 58.6% on days 1, 4, and 7 of ICU admission, respectively), while the incidence of limb skeletal muscle dysfunction showed an increasing trend (54.3% and 62.1% on days 4 and 7 of ICU admission, respectively), with a probability of simultaneous occurrence on days 4 and 7 of ICU admission were 32.6% and 34.5%, respectively. The UCR on day 7 of ICU admission was significantly higher than that on day 1 [121.77 (95.46, 164.55) vs. 97.00 (70.26, 130.50)], and RF-CSA atrophy rate on day 7 was significantly higher than that on day 4 [%: -39.7 (-52.4, -22.1) vs. -26.5 (-40.2, -16.4)]. RF-CSA was significantly lower on day 7 compared to day 1 [cm2: 1.3 (1.0, 2.5) vs. 2.1 (1.7, 2.9)], with all differences being statistically significant (all P < 0.05). Pearson correlation analysis showed that RF-CSA on day 7 of ICU admission was negatively associated with the UCR on the same day (r = -0.407, P = 0.029). Diaphragmatic dysfunction in patients with sepsis occurred early and can be improved. Limb skeletal muscle dysfunction occurred relatively later and progresses progressively. The RF-CSA on day 7 of ICU admission may be a reliable measure of limb skeletal muscle dysfunction in patients with sepsis, can be an indicator of early identification and diagnosis of ICU-acquired weakness (ICU-AW). Continuous loss of muscle mass occurring in septic patients is mainly associated with persistent organismal catabolism, and undergoes significant changes around a week in ICU.

Assessment of muscle dysfunction in COPD patients: A case-control study

Introduction: peripheral muscle dysfunction satellite of chronic obstructive pulmonary disease (COPD) has emerged in recent years as a major factor which limits patients' ability to exercise. Methods: This study is a case-control investigation of the associations between COPD and muscle dysfunction. Cases and control subjects were recruited to evaluate their body composition using bioelectrical impedance (BIA). Quadriceps strength and endurance tests were performed. Dyspnoea was estimated by the mMRC scale. The patients were redirected from the department of pulmonary diseases of Batna, Algeria. The healthy subjects were volunteers without any lung, heart or systemic diseases or handicap in physical effort. Results: 175 patients with stable COPD (9 female and 166 male) aged between 40–86 years, mean FEV1 52 ± 21% and 175 age-and-sex-matched healthy subjects (FEV1: 91± 9%) were included in this study. The cigarette consumption was 35 (20) pack/years in COPD patients vs 15 (15) pack/years in healthy subjects. The classification of airflow limitation showed that 19.43% of patients were classified GOLD I, 30.29% (GOLD II), 33.71% (GOLD III), and 16.57% (GOLD IV). 22. 85% of COPD patients were classified in (category A) ,17.14% (category B) ,16.57% (category C) and 43.42% (category D). fat-free mass index (FFMI) was 19.3 (1.6) kg/m2 in COPD patients vs 18 (4.7) kg/m2 in controls. Quadriceps strength was 109.27 (42.8) Nm in COPD patients vs 141.6 (15) Nm in healthy subjects. The quadriceps endurance was 3.75 (1.14) min in patients vs 16.6 (15) min in controls. Conclusion: This study supports the idea that skeletal muscle mass, quadriceps strength and endurance, were adversely affected in patients with COPD.

Diaphragm Ultrasound in Different Clinical Scenarios: A Review with a Focus on Older Patients.

Diaphragm muscle dysfunction is increasingly recognized as a fundamental marker of several age-related diseases and conditions including chronic obstructive pulmonary disease, heart failure and critical illness with respiratory failure. In older individuals with physical frailty and sarcopenia, the loss of muscle mass and function may also involve the diaphragm, contributing to respiratory dysfunction. Ultrasound has recently emerged as a feasible and reliable strategy to visualize diaphragm structure and function. In particular, it can help to predict the timing of extubation in patients undergoing mechanical ventilation in intensive care units (ICUs). Ultrasonographic evaluation of diaphragmatic function is relatively cheap, safe and quick and can provide useful information for real-time monitoring of respiratory function. In this review, we aim to present the current state of scientific evidence on the usefulness of ultrasound in the assessment of diaphragm dysfunction in different clinical settings, with a particular focus on older patients. We highlight the importance of the qualitative information gathered by ultrasound to assess the integrity, excursion, thickness and thickening of the diaphragm. The implementation of bedside diaphragm ultrasound could be useful for improving the quality and appropriateness of care, especially in older subjects with sarcopenia who experience acute respiratory failure, not only in the ICU setting.

Skeletal Muscle Texture Assessment Using Ultrasonography: Comparison with Magnetic Resonance Imaging in Chronic Kidney Disease.

Skeletal muscle dysfunction is common in chronic kidney disease (CKD). Of interest is the concept of "muscle quality," of which measures include ultrasound-derived echo intensity (EI). Alternative parameters of muscle texture, for example, gray level of co-occurrence matrix (GCLM), are available and may circumvent limitations in EI. The validity of EI is limited in humans, particularly in chronic diseases. This study aimed to investigate the associations between ultrasound-derived parameters of muscle texture with MRI. Images of the thigh were acquired using a 3 Tesla MRI scanner. Quantification of muscle (contractile), fat (non-contractile), and miscellaneous (connective tissue, fascia) components were estimated. Anatomical rectus femoris cross-sectional area was measured using B-mode 2D ultrasonography. To assess muscle texture, first (i.e., EI)- and second (i.e., GLCM)-order statistical analyses were performed. Fourteen participants with CKD were included (age: 58.0 ± 11.9 years, 50% male, eGFR: 27.0 ± 7.4 ml/min/1.73m2, 55% Stage 4). Higher EI was associated with lower muscle % (quadriceps: β = -.568, p = .034; hamstrings: β = -.644, p = .010). Higher EI was associated with a higher fat % in the hamstrings (β = -.626, p = .017). A higher angular second moment from GLCM analysis was associated with greater muscle % (β = .570, p = .033) and lower fat % (β = -.534, p = .049). A higher inverse difference moment was associated with greater muscle % (β = .610, p = .021 and lower fat % (β = -.599, p = .024). This is the first study to investigate the associations between ultrasound-derived parameters of muscle texture with MRI. Our preliminary findings suggest ultrasound-derived texture analysis provides a novel indicator of reduced skeletal muscle % and thus increased intramuscular fat.

Anatomical factors influencing temporomandibular joint clicking in young adults: temporomandibular joint structure disorder or lateral pterygoid muscle dysfunction?

Objective: This study aimed to investigate the selected anatomical factors that can potentially influence temporomandibular joint (TMJ) clicking in young adults by assessing TMJ structures and lateral pterygoid muscle (LPM) function using magnetic resonance imaging (MRI). Methods: The patients were divided into four groups: the healthy control group; the clicking on mouth opening group; the clicking on mouth closing group; and the clicking on mouth opening and closing group. Additionally, we used clinical palpation to evaluate the masticatory muscles' functional state and employed MRI using the OCOR-T1WI-FSE-CLOSED, OSAG-PDW-FSE-CLOSED, and OSAG-PDW-FSE-OPEN sequences to analyze the texture of the lateral pterygoid muscle (LPM). Results: The proportion of any articular disc or condylar morphology class did not differ significantly between the TMJ clicking and HC groups. The articular disc position did not differ significantly between the TMJ clicking and HC groups. In the TMJ clicking group, the presence of masticatory muscle dysfunction differed significantly between the clicking and non-clicking sides. Moreover, the LPM accounted for the highest proportion among masticatory muscles with tenderness in all TMJ clicking subgroups (77.78%-100%). Therefore, in the TMJ clicking group, the LPM texture was less defined, more uniform in gray scale, and more similar to local texture (p < 0.0001). Conclusion: The occurrence of TMJ clicking in young adults is unrelated to the TMJ structure but related to the function of masticatory muscles, particularly the LPM.

RNA-sequencing revisited data shed new light on wooden breast myopathy

Wooden Breast (WB) abnormality represents one of the major challenges that the poultry industry has faced in the last 10 years. Despite the enormous progress in understanding the mechanisms underlying WB, the precise initial causes remain to be clarified. In this scenario, the present research is intended to characterize the gene expression profiles of broiler Pectoralis major muscles affected by WB, comparing them to the unaffected counterpart, to provide new insights into the biological mechanisms underlying this defect and potentially identifying novel genes likely involved in its occurrence. To this purpose, data obtained in a previous study through the RNA-sequencing technology have been used to identify differentially expressed genes (DEGs) between 6 affected and 5 unaffected broilers' breast muscles, by using the newest reference genome assembly for Gallus gallus (GRCg7b). Also, to deeply investigate molecular and biological pathways involved in the WB progression, pathways analyses have been performed. The results achieved through the differential gene expression analysis mainly evidenced the downregulation of glycogen metabolic processes, gluconeogenesis, and tricarboxylic acid cycle in WB muscles, thus corroborating the evidence of a dysregulated energy metabolism characterizing breasts affected by this abnormality. Also, genes related to hypertrophic muscle growth have been identified as differentially expressed (e.g., WFIKKN1). Together with that, a downregulation of genes involved in mitochondrial biogenesis and functionality has been detected. Among them, PPARGC1A and PPARGC1B chicken genes are particularly noteworthy. These genes not only have essential roles in regulating mitochondrial biogenesis but also play pivotal roles in maintaining glucose and energy homeostasis. In view of that, their downregulation in WB-affected muscle may be considered as potentially related to both the mitochondrial dysfunction and altered glucose metabolism in WB muscles, and their key involvement in the molecular alterations characterizing this muscular abnormality might be hypothesized.

Cystine/glutamate antiporter xCT controls skeletal muscle glutathione redox, bioenergetics and differentiation

Cysteine, the rate-controlling amino acid in cellular glutathione synthesis is imported as cystine, by the cystine/glutamate antiporter, xCT, and subsequently reduced to cysteine. As glutathione redox is important in muscle regeneration in aging, we hypothesized that xCT exerts upstream control over skeletal muscle glutathione redox, metabolism and regeneration. Bioinformatic analyses of publicly available datasets revealed that expression levels of xCT and GSH-related genes are inversely correlated with myogenic differentiation genes. Muscle satellite cells (MuSCs) isolated from Slc7a11sut/sut mice, which harbour a mutation in the Slc7a11 gene encoding xCT, required media supplementation with 2-mercaptoethanol to support cell proliferation but not myotube differentiation, despite persistently lower GSH. Slc7a11sut/sut primary myotubes were larger compared to WT myotubes, and also exhibited higher glucose uptake and cellular oxidative capacities. Immunostaining of myogenic markers (Pax7, MyoD, and myogenin) in cardiotoxin-damaged tibialis anterior muscle fibres revealed greater MuSC activation and commitment to differentiation in Slc7a11sut/sut muscle compared to WT mice, culminating in larger myofiber cross-sectional areas at 21 days post-injury. Slc7a11sut/sut mice subjected to a 5-week exercise training protocol demonstrated enhanced insulin tolerance compared to WT mice, but blunted muscle mitochondrial biogenesis and respiration in response to exercise training. Our results demonstrate that the absence of xCT inhibits cell proliferation but promotes myotube differentiation by regulating cellular metabolism and glutathione redox. Altogether, these results support the notion that myogenesis is a redox-regulated process and may help inform novel therapeutic approaches for muscle wasting and dysfunction in aging and disease.

Lipidomics and single-cell RNA sequencing reveal lipid and cell dynamics of porcine glycerol-injured skeletal muscle regeneration model

AimsIntramuscular fat (IMF) infiltration and extracellular matrix (ECM) deposition are characteristic features of muscle dysfunction, such as muscular dystrophy and severe muscle injuries. However, the underlying mechanisms of cellular origin, adipocyte formation and fibrosis in skeletal muscle are still unclear. Main methodsPigs were injected with 50 % glycerol (GLY) to induce skeletal muscle injury and regeneration. The acyl chain composition was analyzed by lipidomics, and the cell atlas and molecular signatures were revealed via single-cell RNA sequencing (scRNA-seq). Adipogenesis analysis was performed on fibroblast/fibro-adipogenic progenitors (FAPs) isolated from pigs. Key findingsThe porcine GLY-injured skeletal muscle regeneration model was characterized by IMF infiltration and ECM deposition. Skeletal muscle stem cells (MuSCs) and FAP clusters were analyzed to explore the potential mechanisms of adipogenesis and fibrosis, and it was found that the TGF-β signaling pathway might be a key switch that regulates differentiation. Consistently, activation of the TGF-β signaling pathway increased SMAD2/3 phosphorylation and inhibited adipogenesis in FAPs, while inhibition of the TGF-β signaling pathway increased the expression of PPARγ and promoted adipogenesis. SignificanceGLY-induced muscle injury and regeneration provides comprehensive insights for the development of therapies for human skeletal muscle dysfunction and fatty infiltration-related diseases in which the TGF-β/SMAD signaling pathway might play a primary regulatory role.

The Application of Surface Electromyography Technology in Evaluating Paraspinal Muscle Function.

Surface electromyography (sEMG) has emerged as a valuable tool for assessing muscle activity in various clinical and research settings. This review focuses on the application of sEMG specifically in the context of paraspinal muscles. The paraspinal muscles play a critical role in providing stability and facilitating movement of the spine. Dysfunctions or alterations in paraspinal muscle activity can lead to various musculoskeletal disorders and spinal pathologies. Therefore, understanding and quantifying paraspinal muscle activity is crucial for accurate diagnosis, treatment planning, and monitoring therapeutic interventions. This review discusses the clinical applications of sEMG in paraspinal muscles, including the assessment of low back pain, spinal disorders, and rehabilitation interventions. It explores how sEMG can aid in diagnosing the potential causes of low back pain and monitoring the effectiveness of physical therapy, spinal manipulative therapy, and exercise protocols. It also discusses emerging technologies and advancements in sEMG techniques that aim to enhance the accuracy and reliability of paraspinal muscle assessment. In summary, the application of sEMG in paraspinal muscles provides valuable insights into muscle function, dysfunction, and therapeutic interventions. By examining the literature on sEMG in paraspinal muscles, this review offers a comprehensive understanding of the current state of research, identifies knowledge gaps, and suggests future directions for optimizing the use of sEMG in assessing paraspinal muscle activity.

Proteomic reference map for sarcopenia research: mass spectrometric identification of key muscle proteins located in the sarcomere, cytoskeleton and the extracellular matrix.

Sarcopenia of old age is characterized by the progressive loss of skeletal muscle mass and concomitant decrease in contractile strength. Age-related skeletal muscle dysfunctions play a key pathophysiological role in the frailty syndrome and can result in a drastically diminished quality of life in the elderly. Here we have used mass spectrometric analysis of the mouse hindlimb musculature to establish the muscle protein constellation at advanced age of a widely used sarcopenic animal model. Proteomic results were further analyzed by systems bioinformatics of voluntary muscles. In this report, the proteomic survey of aged muscles has focused on the expression patterns of proteins involved in the contraction-relaxation cycle, membrane cytoskeletal maintenance and the formation of the extracellular matrix. This includes proteomic markers of the fast versus slow phenotypes of myosin-containing thick filaments and actin-containing thin filaments, as well as proteins that are associated with the non-sarcomeric cytoskeleton and various matrisomal layers. The bioanalytical usefulness of the newly established reference map was demonstrated by the comparative screening of normal versus dystrophic muscles of old age, and findings were verified by immunoblot analysis.

Characterization and evaluation of MFG-E8 protein-derived peptides: From isolation to functional assessment in skeletal muscle lipid metabolism

This research investigated preparation, identification and relative properties of milk fat globule epidermal growth factor Ⅷ (MFG-E8) protein-derived peptides. MFG-E8 protein was extracted from bovine milk and peptides were isolated and obtained using an in vitro simulating gastrointestinal digestion model, the peptide sequence was then identified. High-abundance MFG-E8 peptides bind well to the protein domain of pancreatic lipase was selected. Enzyme kinetic studies exhibited that the inhibition effect of KDPG and YAR on pancreatic lipase activity was reversible and non-competitive inhibition. Fluorescence spectroscopic analysis showed that KDPG and YAR acted as fluorescence quenchers of pancreatic lipase and exhibited certain dose-dependent effect. In vivo animal experiments further verified the regulatory effects of MFG-E8 peptides on lipid metabolism and skeletal muscle profiles, which provided the potential role of KDPG and YAR in regulating lipid metabolism and alleviating skeletal muscle dysfunction via AMPK/SREBP-1/SCD-1 signaling pathway.

The effect of suboccipital muscle dysfunction on the biomechanics of the upper cervical spine: a study based on finite element analysis

ObjectiveMuscle dysfunction caused by repetitive work or strain in the neck region can interfere muscle responses. Muscle dysfunction can be an important factor in causing cervical spondylosis. However, there has been no research on how the biomechanical properties of the upper cervical spine change when the suboccipital muscle group experiences dysfunction. The objective of this study was to investigate the biomechanical evidence for cervical spondylosis by utilizing the finite element (FE) approach, thus and to provide guidance for clinicians performing acupoint therapy.MethodsBy varying the elastic modulus of the suboccipital muscle, the four FE models of C0-C3 motion segments were reconstructed under the conditions of normal muscle function and muscle dysfunction. For the two normal condition FE models, the elastic modulus for suboccipital muscles on both sides of the C0-C3 motion segments was equal and within the normal range In one muscle dysfunction FE model, the elastic modulus on both sides was equal and greater than 37 kPa, which represented muscle hypertonia; in the other, the elastic modulus of the left and right suboccipital muscles was different, indicating muscle imbalance. The biomechanical behavior of the lateral atlantoaxial joint (LAAJ), atlanto-odontoid joint (ADJ), and intervertebral disc (IVD) was analyzed by simulations, which were carried out under the six loadings of flexion, extension, left and right lateral bending, left and right axial rotation.ResultsUnder flexion, the maximum stress in LAAJ with muscle imbalance was higher than that with normal muscle and hypertonia, while the maximum stress in IVD in the hypertonic model was higher than that in the normal and imbalance models. The maximum stress in ADJ was the largest under extension among all loadings for all models. Muscle imbalance and hypertonia did not cause overstress and stress distribution abnormalities in ADJ.ConclusionMuscle dysfunction increases the stress in LAAJ and in IVD, but it does not affect ADJ.

CaMKIIβ deregulation contributes to neuromuscular junction destabilization in Myotonic Dystrophy type I

BackgroundMyotonic Dystrophy type I (DM1) is the most common muscular dystrophy in adults. Previous reports have highlighted that neuromuscular junctions (NMJs) deteriorate in skeletal muscle from DM1 patients and mouse models thereof. However, the underlying pathomechanisms and their contribution to muscle dysfunction remain unknown.MethodsWe compared changes in NMJs and activity-dependent signalling pathways in HSALR and Mbnl1ΔE3/ΔE3 mice, two established mouse models of DM1.ResultsMuscle from DM1 mouse models showed major deregulation of calcium/calmodulin-dependent protein kinases II (CaMKIIs), which are key activity sensors regulating synaptic gene expression and acetylcholine receptor (AChR) recycling at the NMJ. Both mouse models exhibited increased fragmentation of the endplate, which preceded muscle degeneration. Endplate fragmentation was not accompanied by changes in AChR turnover at the NMJ. However, the expression of synaptic genes was up-regulated in mutant innervated muscle, together with an abnormal accumulation of histone deacetylase 4 (HDAC4), a known target of CaMKII. Interestingly, denervation-induced increase in synaptic gene expression and AChR turnover was hampered in DM1 muscle. Importantly, CaMKIIβ/βM overexpression normalized endplate fragmentation and synaptic gene expression in innervated Mbnl1ΔE3/ΔE3 muscle, but it did not restore denervation-induced synaptic gene up-regulation.ConclusionsOur results indicate that CaMKIIβ-dependent and -independent mechanisms perturb synaptic gene regulation and muscle response to denervation in DM1 mouse models. Changes in these signalling pathways may contribute to NMJ destabilization and muscle dysfunction in DM1 patients.

Saururus chinensis (Lour.) Baill. extract promotes skeletal muscle cell differentiation by positively regulating mitochondrial biogenesis and AKT/mTOR signaling in vitro.

Promotion of myoblast differentiation by activating mitochondrial biogenesis and protein synthesis signaling pathways provides a potential alternative strategy to balance energy and overcome muscle loss and muscle disorders. Saururus chinensis (Lour.) Baill. extract (SCE) has been used extensively as a traditional herbal medicine and has several physiological activities, including anti‑asthmatic, anti‑oxidant, anti‑inflammatory, anti‑atopic, anticancer and hepatoprotective properties. However, the effects and mechanisms of action of SCE on muscle differentiation have not yet been clarified. In the present study, it was investigated whether SCE affects skeletal muscle cell differentiation through the regulation of mitochondrial biogenesis and protein synthesis in murine C2C12 myoblasts. The XTT colorimetric assay was used to determine cell viability, and myosin heavy chain (MyHC) levels were determined using immunocytochemistry. SCE was applied to C2C12 myotube at different concentrations (1, 5, or 10 ng/ml) and times (1,3, or 5 days). Reverse transcription‑quantitative PCR and western blotting were used to analyze the mRNA and protein expression change of factors related to differentiation, mitochondrial biogenesis and protein synthesis. Treatment of C2C12 cells with SCE at 1,5, and 10 ng/ml did not affect cell viability. SCE promoted C2C12 myotube formation and significantly increased MyHC expression in a concentration‑ and time‑dependent manner. SCE significantly increased the mRNA and protein expression of muscle differentiation‑specific markers, such as MyHC, myogenic differentiation 1, myogenin, Myogenic Factor 5, and β‑catenin, mitochondrial biosynthesis‑related factors, such as peroxisome proliferator‑activated receptor‑gamma coactivator‑1α, nuclear respirator factor‑1, AMP‑activated protein kinase phosphorylation, and histone deacetylase 5 and AKT/mTOR signaling factors related to protein synthesis. SCE may prevent skeletal muscle dysfunction by enhancing myoblast differentiation through the promotion of mitochondrial biogenesis and protein synthesis.

The role of cardiac PET in diagnosis and prognosis of patients with ischemia with no obstructive coronary arteries (INOCA)

Chest pain, a common symptom in cardiovascular care, often leads to the investigation of obstructive coronary artery disease (CAD). However, many patients experience chest pain without obstructive CAD, termed INOCA (Ischemia with Non-Obstructive Coronary Arteries) or CMD (Coronary Microvascular Dysfunction). INOCA can be attributed to endothelial dysfunction, vascular smooth muscle dysfunction, or both, affecting about 20–30 % of patients with nonobstructive CAD. The diagnostic approach for INOCA includes both invasive and non-invasive methods, with cardiac PET (Positron Emission Tomography) playing a significant role in risk stratification and management. PET evaluates various parameters like myocardial blood flow under stress and rest, myocardial flow reserve, and myocardial ischemia. Such comprehensive assessment is essential in accurately diagnosing and managing INOCA, considering the complexity of this condition.

Associations of appendicular lean mass and abdominal adiposity with insulin resistance in older adults: A cross-sectional study.

Loss of lean muscle mass and accumulation of adipose tissue are changes associated with aging. Previous studies have documented various components of body composition as predictors for insulin resistance. The objective of this study was to investigate whether components of body composition-appendicular lean mass (ALM) and/or abdominal fat mass (AFM)-correlate with insulin resistance in older men and women. This was a cross-sectional study of 92 older men and women. Weight was classified according to body mass index (BMI)-normal (BMI <25), overweight (BMI 25-30), and obese (BMI >30). All body composition data was determined by dual energy x-ray absorptiometry (DEXA), and insulin resistance was assessed by the homeostatic model assessment of insulin resistance (HOMA-IR). Multivariable regression models with two-way interaction terms were employed to assess whether the associations between components of body composition and log HOMA varied by BMI categories. Adjusted regression showed that log HOMA was significantly associated with AFM (estimate ± standard error: 0.055 ± 0.026) and ALM (0.057 ± 0.029) for the overweight participants (p-values <0.05). Additionally, the adjusted associations between log HOMA and ALM were significantly greater for participants who were either obese or overweight compared to those with a normal BMI (p<0.002). Less consistent relationships were observed between insulin resistance and abdominal fat mass across BMI categories, whereas more consistent associations were observed between insulin resistance and appendicular lean mass in individuals with greater BMI. Further research is needed to clarify if lipid deposition within muscle tissue promotes muscle dysfunction and thereby increases risk for insulin resistance.

Altered skeletal muscle function and beneficial effects of exercise training in a rat model of induced pulmonary emphysema.

Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow obstruction and development of emphysema. Among the comorbidities associated with COPD, skeletal muscle dysfunction is known to affect exercise capacity and the survival rate of patients. Pulmonary rehabilitation (PR), via exercise training, is essential for COPD patients. However, the response to PR is most often moderate. An animal model that recapitulates critical features of chronic human disease and provides access to muscle function should therefore be useful to improve PR benefits. We used a rat model of induced emphysema based on pulmonary instillations of elastase (ELA) and lipopolysaccharides (LPS). We assessed the long-term effects of ELA/LPS and the potential effectiveness of endurance training on the skeletal muscle function. Invivo strength of the animals, and exvivo contractility, endurance, type 1 fiber proportion, fiber cross-sectional area, and capillarization of both soleus and extensor digitorum longus (EDL) were assessed. An impaired overall muscle strength with decreased force, reduced capillarization, and atrophy of type 1 fiber of EDL was observed in ELA/LPS rats. Soleus was not affected. Endurance training was able to reduce fatigability, and increase type 1 fiber proportion and capillarization of soleus, and improve force, endurance, and capillarization of EDL in control and ELA/LPS rats. Our rat model of induced emphysema, which shares some features with the phenotype present in patients with COPD, could represent a suitable model to study skeletal muscle dysfunction and the effects of exercise training on muscle function in patients.

Lack of compensatory mitophagy in skeletal muscles during sepsis.

Skeletal muscle dysfunction is a major problem in critically ill patients suffering from sepsis. This condition is associated with mitochondrial dysfunction and increased autophagy in skeletal muscles. Autophagy is a proteolytic mechanism involved in eliminating dysfunctional cellular components, including mitochondria. The latter process, referred to as mitophagy, is essential for maintaining mitochondrial quality and skeletal muscle health. Recently, a fluorescent reporter system called mito-QC (i.e. mitochondrial quality control) was developed to specifically quantify mitophagy levels. In the present study, we used mito-QC transgenic mice and confocal microscopy to morphologically monitor mitophagy levels during sepsis. To induce sepsis, Mito-QC mice received Escherichia coli lipopolysaccharide (10mgkg-1 i.p.) or phosphate-buffered saline and skeletal muscles (hindlimb and diaphragm) were excised 48h later. In control groups, there was a negative correlation between the basal mitophagy level and overall muscle mitochondrial content. Sepsis increased general autophagy in both limb muscles and diaphragm but had no effect on mitophagy levels. Sepsis was associated with a downregulation of certain mitophagy receptors (Fundc1, Bcl2L13, Fkbp8 and Phbb2). The present study suggests that general autophagy and mitophagy can be dissociated from one another, and that the characteristic accumulation of damaged mitochondria in skeletal muscles under the condition of sepsis may reflect a failure of adequate compensatory mitophagy. KEY POINTS: There was a negative correlation between the basal level of skeletal muscle mitophagy and the mitochondrial content of individual muscles. Mitophagy levels in limb muscles and the diaphragm were unaffected by lipopolysaccharide (LPS)-induced sepsis. With the exception of BNIP3 in sepsis, LPS administration induced either no change or a downregulation of mitophagy receptors in skeletal muscles.

Cerium Oxide Nanozymes Improve Skeletal Muscle Function in Gestational Diabetic Offspring by Attenuating Mitochondrial Oxidative Stress.

Gestational diabetes mellitus (GDM) is a significant complication during pregnancy that results in abnormalities in the function of multiple systems in the offspring, which include skeletal muscle dysfunction and reduced systemic metabolic capacity. One of the primary causes behind this intergenerational effect is the presence of mitochondrial dysfunction and oxidative stress in the skeletal muscle of the offspring due to exposure to a high-glucose environment in utero. Cerium oxide (CeO2) nanozymes are antioxidant agents with polymerase activity that have been widely used in the treatment of inflammatory and aging diseases. In this study, we synthesized ultrasmall particle size CeO2 nanozymes and applied them in GDM mouse offspring. The CeO2 nanozymes demonstrated an ability to increase insulin sensitivity and enhance skeletal muscle motility in GDM offspring by improving mitochondrial activity, increasing mitochondrial ATP synthesis function, and restoring abnormal mitochondrial morphology. Furthermore, at the cellular level, CeO2 nanozymes could ameliorate metabolic dysregulation and decrease cell differentiation in adult muscle cells induced by hyperglycemic stimuli. This was achieved through the elimination of endogenous reactive oxygen species (ROS) and an improvement in mitochondrial oxidative respiration function. In conclusion, CeO2 nanozymes play a crucial role in preserving muscle function and maintaining the metabolic stability of organisms. Consequently, they serve to reverse the negative effects of GDM on skeletal muscle physiology in the offspring.

Cyclo His-Pro Attenuates Muscle Degeneration in Murine Myopathy Models.

Among the inherited myopathies, a group of muscular disorders characterized by structural and metabolic impairments in skeletal muscle, Duchenne muscular dystrophy (DMD) stands out for its devastating progression. DMD pathogenesis is driven by the progressive degeneration of muscle fibers, resulting in inflammation and fibrosis that ultimately affect the overall muscle biomechanics. At the opposite end of the spectrum of muscle diseases, age-related sarcopenia is a common condition that affects an increasing proportion of the elderly. Although characterized by different pathological mechanisms, DMD and sarcopenia share the development of progressive muscle weakness and tissue inflammation. Here, the therapeutic effects of Cyclo Histidine-Proline (CHP) against DMD and sarcopenia are evaluated. In the mdx mouse model of DMD, it is shown that CHP restored muscle contractility and force production, accompanied by the reduction of fibrosis and inflammation in skeletal muscle. CHP furthermore prevented the development of cardiomyopathy and fibrosis in the diaphragm, the two leading causes of death for DMD patients. CHP also attenuated muscle atrophy and functional deterioration in a mouse model of age-related sarcopenia. These findings from two different models of muscle dysfunction hence warrant further investigation into the effects of CHP on muscle pathologies in animal models and eventually in patients.