A specific skeletal muscle dysfunction in iron deficiency.
Explore the source record for details and available documents.
Anemia, Hypochromic↗
SEARCH · Search PubMed
Results for “Skeletal muscle dysfunction”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Author Correction: Impaired cAMP-PKA-CREB1 signalling drives mitochondrial dysfunction in skeletal muscle during cancer cachexia.
Explore the source record for details and available documents.
Published Erratum↗
Exerkine dysregulation links visceral adiposity to skeletal muscle impairment in end-stage heart failure with reduced ejection fraction: proteomic evidence for a cardio-adipose-muscle axis.
BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) is associated with profound alterations in body composition, skeletal muscle dysfunction, and impaired exercise capacity. Exerkines representing exercise-responsive signaling molecules released by skeletal muscle, adipose tissue, and other organs may mediate systemic metabolic communication between tissues. However, their role in advanced HFrEF and their relationship with adiposity and skeletal muscle characteristics remain poorly understood. METHODS: We studied 73 patients with end-stage HFrEF and 16 healthy controls. Body composition was assessed using computed tomography, including visceral (VAT), subcutaneous (SAT), and epicardial adipose tissue (EAT), as well as skeletal muscle quantity (psoas muscle index, PMI) and quality (psoas muscle density, PMD). Functional performance was evaluated using handgrip strength (HGT) and the 6-min walk test (6MWT). Circulating exerkines were quantified using the Olink technology. Associations between proteins and clinical variables were assessed using age- and creatinine-adjusted linear models with false discovery rate correction. RESULTS: Among patients with HFrEF, 36% were obese and 38% exhibited central obesity independent of BMI. Muscle strength and muscle quality were strongly associated with functional capacity. VAT correlated with muscle mass but not with muscle quality or performance. Compared with controls, HFrEF patients demonstrated elevated inflammatory and metabolic stress-related exerkines including CXCL8, CCL2, IL-6, TNF, IL-15, GDF15, FGF21, ANGPTL4, CTSB, DCN, and resistin. In contrast, proteins associated with muscle integrity and regenerative signaling (myostatin, BDNF, IL-7, SPARC) were significantly reduced. In HFrEF patients leptin strongly correlated with adiposity measures. Metabolic stress mediators (GDF15, IL-15, FGF21, CTSB) were inversely associated with muscle quality and functional performance, whereas myostatin positively correlated with muscle quality, strength, and exercise capacity. BDNF was inversely associated with frailty. CONCLUSIONS: Advanced HFrEF is characterized by a dysregulated exerkine network linking adiposity, skeletal muscle quality, and functional performance. Four biologically coherent axes were identified: a leptin-driven adiposity axis, a metabolic stress-muscle quality axis, a myostatin-related muscle function axis, and a neurotrophic frailty axis. These findings support the presence of a systemic cardio-adipose-muscle signaling network in end-stage HFrEF and identify candidate molecular mediators of sarcopenia and functional decline.
Humans↗
Age-induced changes in skeletal muscle mitochondrial DNA synthesis, quantity, and quality in genetically unique rats.
Mitochondrial genomic integrity is a key element of physiological processes and health. Changes in the half-life of the mitochondrial genome are implicated in the generation and accumulation of age-induced mitochondrial DNA (mtDNA) mutations, which are implicated in skeletal muscle aging and sarcopenia. There are conflicting data on the half-life of mtDNA, and there is limited information on how aging affects half-life in skeletal muscle. We hypothesized that skeletal muscle mtDNA synthesis rates would decrease with age in both female and male rats concomitant with changes in mtDNA integrity reflected in mtDNA copy number and mutation frequency. We measured mitochondrial genome half-life using stable isotope labeling over a period of 14 days and assessed mtDNA copy number and deletion mutation frequency using digital PCR in the quadriceps muscle of 9-month-old and 26-month-old male and female OKC-HET rats. We found a significant age-related increase in mtDNA half-life, from 132 days at 9 months to 216 days at 26 months of age in OKC-HET quadriceps. Concomitant with the increase in mtDNA half-life, we found an age-related increase in mtDNA deletion mutation frequency in both male and female rats. Notably, 26-month-old female rats had a lower mutation frequency than male rats, and there were no changes in mtDNA copy number with sex, age, or mitochondrial genotype. These data reveal several key findings: (1) mtDNA turnover in rat skeletal muscle decreases with age, (2) mtDNA half-lives in skeletal muscle are approximately an order of magnitude longer than what is reported for other tissues, and (3) muscle mtDNA turnover differs significantly from the turnover of other mitochondrial macromolecules including components of the mitochondrial nucleoid. These findings provide insight into the factors driving age-induced mtDNA mutation accumulation, which contribute to losses of mitochondrial genomic integrity and may play a role in skeletal muscle dysfunction.
Animals↗
Celery seed extract attenuates sarcopenic obesity and age-related sarcopenia by reducing intramuscular lipid accumulation in mice.
BACKGROUND & AIMS: Sarcopenia is characterized by progressive loss of skeletal muscle mass and function and is increasingly recognized to be influenced by metabolic disturbances associated with aging and obesity. Intramuscular lipid accumulation has emerged as a key pathological feature linking metabolic dysfunction to skeletal muscle deterioration. Celery seed extract (CSE) possesses anti-obesity, anti-inflammatory, and antioxidant properties; however, its potential role in skeletal muscle metabolism has not been well investigated. This study aimed to determine whether CSE attenuates skeletal muscle deterioration associated with obesity and aging through modulation of intramuscular lipid accumulation and related metabolic pathways. METHODS: Diet-induced obese mice and naturally aged mice were used to evaluate the effects of CSE supplementation. Skeletal muscle mass, grip strength, muscle morphology, intramuscular lipid content, mitochondrial metabolic signaling, inflammatory responses, and muscle protein turnover pathways were assessed using biochemical, molecular, and histological analyses. RESULTS: CSE supplementation significantly improved skeletal muscle mass, grip strength, and muscle fiber cross-sectional area in both obese and aged mice. These improvements were accompanied by reduced intramuscular triglyceride and cholesterol accumulation. Mechanistically, CSE improved mitochondrial metabolic signaling by activating the AMPK-PGC-1α pathway and increasing mitochondrial oxidative phosphorylation proteins. In addition, CSE suppressed inflammatory signaling pathways, including MAPK activation and NLRP3 inflammasome signaling, and improved muscle proteostasis by enhancing myogenic regulators while reducing the expression of proteolytic factors such as MuRF1, Atrogin-1, and myostatin. Correlation analyses further indicated that intramuscular lipid accumulation was closely associated with mitochondrial dysfunction, inflammatory activation, and muscle atrophy. CONCLUSIONS: These findings demonstrate that CSE alleviates skeletal muscle deterioration in both obesity- and aging-associated sarcopenia by reducing intramuscular lipid accumulation and improving mitochondrial metabolism, inflammatory responses, and muscle protein turnover. Targeting intramuscular lipid accumulation may therefore represent a promising nutritional strategy for preventing sarcopenia associated with metabolic and aging-related stress.
AMPK–PGC-1α↗
Neonatal gene therapy with AAV2/8-LSPhGAA improves hypertrophic cardiomyopathy in the Gaac.1826dupA knock-in murine model.
Pompe disease (PD) results from lysosomal acid α-glucosidase (GAA) deficiency, causing lysosomal glycogen accumulation in cardiac and skeletal muscles. We previously characterized a murine model carrying the orthologous human infantile-onset PD (IOPD) pathogenic variant, c.1826dupA (p.Y609*), introduced into the mouse Gaa gene. Compared to wild-type (WT; C57BL/6NJ) controls, Gaac.1826dupA mice exhibit reduced GAA activity and develop early-onset hypertrophic cardiomyopathy-evidenced by increased left ventricular wall thickness and left ventricular mass index (LVMI)- as well as impaired grip strength and gait abnormalities. To benchmark the model's disease fidelity and assess its responsiveness to established therapeutic intervention, Gaac.1826dupA mice received a single retro-orbital dose of AAV2/8-LSPhGAA (2 × 109 vg/g body weight) at postnatal day 12-14. Twelve weeks post-treatment, mice exhibited supraphysiological GAA enzymatic activity in the heart (550% of WT) and liver (400% of WT) with a 93% reduction in cardiac glycogen. No sex-dependent differences in therapeutic efficacy were observed. Echocardiography revealed robust reversal of cardiac pathology, with wall thicknesses and LVMI values approaching WT levels. In contrast to this profound cardiac rescue, skeletal muscle improvements were modest; while forelimb grip strength remained unchanged, automated gait analysis showed benefit limited to hind paw base of support. These findings demonstrate that the Gaac.1826dupA model mirrors the critical cardiomyopathy characteristic of IOPD. While systemic AAV treatment yields definitive cardiac correction, the partial skeletal muscle response highlights a clear need for optimization. Consequently, the Gaac.1826dupA mouse serves as a high-fidelity platform for evaluating next-generation genomic correction strategies targeting both cardiac and refractory neuromuscular manifestations of PD.
Acid α-glucosidase↗
Treatment updates in myotonic disorders.
Myotonia is delayed muscle relaxation after forceful contraction. It is due to hyperexcitability of the skeletal muscle membrane. It can arise from primary skeletal muscle ion channel dysfunction, involving chloride or sodium channels, but is also a prominent clinical feature in myotonic dystrophies where altered RNA splicing leads to secondary ion channel dysregulation amongst other systemic manifestations. Clinically, myotonia can range from delayed eye opening to a disabling symptom causing impaired mobility, functional difficulty and sometimes pain. It can also be a "hidden disability" with many patients feeling socially embarrassed by "looking healthy", yet being unable to do everyday physical tasks or to do them as effortlessly as their peers. It is a symptom that almost always indicates a genetic diagnosis, although it can occur in acquired conditions, including metabolic and drug-induced causes. To experience myotonia without knowing what it is can be baffling. To receive a genetic diagnosis associated with it can be life changing. Although there is no cure, there are many effective and available symptomatic treatments for myotonia and currently we are in an exciting era of clinical trials for new molecular disease-modifying therapies for myotonic dystrophy type 1. In this review, we consider recent developments in the treatment of myotonic disorders and how they may change clinical practice.
Humans↗
Skeletal muscle calcium metabolism and contractile force in vitamin D-deficient chicks.
The myopathy associated with vitamin D deficiency has not been well characterized, and it is not known if weakness is a result of a specific effect of vitamin D deficiency on skeletal muscle. Chicks were raised from hatching on a vitamin D-deficient diet, and by 3 wk of age were hypocalcemic and appeared weak. Tension generated by triceps surae during repetitive stimulation of posterior tibial nerve was significantly less than that developed by chicks given vitamin D(3) supplements (309 g tension/g wet weight of triceps surae, SD 60, for vitamin D-deficient chicks; 470, SD 77, for vitamin D(3)-treated chicks, P < 0.01). Histochemical and electron microscopic examination of skeletal muscles of these chicks showed no abnormalities, and there were no electrophysiologic evidences of motor nerve or neuromuscular junction dysfunction. The concentration of ATP in skeletal muscle of the vitamin D-deficient chicks (5.75 mumol/g wet weight, SD 0.17) was not significantly different from that in vitamin D-treated chicks (5.60, SD 0.50). There was no correlation between strength and serum calcium, serum inorganic phosphate, or skeletal muscle inorganic phosphate. Relaxation of tension after tetanic stimulation was slowed in the vitamin D-deficient chicks (20.6 ms, SD 1.7, vs. 15.4, SD 1.3, in vitamin D-treated chicks and 15.3, SD 1.0, in normal control chicks), and in vitro (45)Ca(++) transport by sarcoplasmic reticulum from the vitamin D-deficient chicks was reduced. Calcium content of mitochondria prepared from leg muscles of vitamin D-deficient chicks (24 nmol/mg mitochondrial protein, SD 6) was considerably lower than that of mitochondria from normal control chicks (45, SD 8) or from chicks treated with vitamin D for 2 wk or more (66-100, depending upon level and duration of therapy). Treatment of the vitamin D-deficient chicks from hatching with sufficient dietary calcium to produce hypercalcemia did not significantly raise skeletal muscle mitochondrial calcium content (31 nmol/mg mitochondrial protein, SD 7) and did not prevent weakness. These studies demonstrate objective weakness as a result of myopathy in vitamin D-deficient chicks, and provide evidence that vitamin D deficiency has effects on skeletal muscle calcium metabolism not secondary to altered plasma concentrations of calcium and phosphate.
Animals↗
Perspective on Adeno-Associated Virus Capsid Modification for Duchenne Muscular Dystrophy Gene Therapy.
Duchenne muscular dystrophy (DMD) is a X-linked, progressive childhood myopathy caused by mutations in the dystrophin gene, one of the largest genes in the genome. It is characterized by skeletal and cardiac muscle degeneration and dysfunction leading to cardiac and/or respiratory failure. Adeno-associated virus (AAV) is a highly promising gene therapy vector. AAV gene therapy has resulted in unprecedented clinical success for treating several inherited diseases. However, AAV gene therapy for DMD remains a significant challenge. Hurdles for AAV-mediated DMD gene therapy include the difficulty to package the full-length dystrophin coding sequence in an AAV vector, the necessity for whole-body gene delivery, the immune response to dystrophin and AAV capsid, and the species-specific barriers to translate from animal models to human patients. Capsid engineering aims at improving viral vector properties by rational design and/or forced evolution. In this review, we discuss how to use the state-of-the-art AAV capsid engineering technologies to overcome hurdles in AAV-based DMD gene therapy.
Animals↗
Myoglobin: methods and diagnostic uses.
Myoglobin is the oxygen-binding protein characteristic of skeletal and cardiac muscle. With muscle disease or dysfunction, myoglobin may enter the circulation, and after renal clearance, it may also appear in the urine. Therefore, the presence of myoglobinemia and myoglobinuria may serve as indicators of the presence and severity of muscle disease. With newly developed methods of detection, myoglobinemia and myoglobinuria are now recognized as complications of trauma, ischemia, surgery, states of exertion and stress, metabolic abnormalities, inherited enzyme disorders, toxin and drug actions, and inflammatory states. Infarction of the heart muscle also can be detected by myoglobin assay. Persistent myoglobinuric states may be complicated by renal failure and electrolyte imbalance. The diagnosis of myoglobinemia and myoglobinuria can be now confirmed with the use of immunoassay techniques. Although not yet widely available, they offer the possibility of the specificity and sensitivity needed for clinical use.
Humans↗
Delivery of recombinant adeno-associated virus vectors to rat diaphragm muscle via direct intramuscular injection.
The diaphragm is the most important inspiratory muscle in all mammals, and ventilatory insufficiency caused by diaphragm dysfunction is the leading cause of morbidity and mortality in many genetic and acquired diseases affecting skeletal muscle. Currently, pharmacological inhibitors, genetically modified animals, and invasive procedures are used to study disorders affecting the diaphragm. However, these methodologies can be problematic because of off-target drug effects and the possible nonphysiological consequences of lifelong genetic alterations. Therefore, alternative methods to study this important respiratory muscle are needed. To resolve this, we have developed a methodology to deliver recombinant adeno-associated virus (rAAV) vectors to the rat diaphragm via direct intramuscular injection. We hypothesized that by direct injection of rAAV into the muscle we can selectively target the diaphragm and establish a novel experimental method for studying signaling pathways and also provide a strategy for effectively using rAAV to protect the diaphragm against disease. This report describes the methods and evidence to support the use of rAAV as a therapeutic intervention to study rat diaphragm biology during conditions that promote diaphragm dysfunction.
Animals↗
Electromyographic abnormalities in osteosarcoma arising in Paget disease of the vertebral column.
The case of a patient with low back pain and Paget disease of the L5, S1 vertebrae is presented. Electromyography revealed dysfunction in both the paraspinal and gluteal muscles. Postmortem examination showed sarcomatous transformation of the vertebrae with nerve root compression and skeletal muscle infiltration by tumor. The electromyographic abnormalities are correlated with the pathologic findings. The clinical features of neurologic dysfunction in Paget disease of the vertebral column and in osteosarcoma arising in Paget disease of the vertebral column are reviewed. Electromyography can provide valuable information in the evaluation of the patient with Paget disease of the vertebral column who is suspected of having neurologic dysfunction.
Electromyography↗
Neuromuscular dysfunction induced by acetylcholinesterase inhibition.
The organophosphate cholinesterase inhibitor paraoxon produces a dose-dependent necrosis in rat skeletal muscle fibers after a single administration. The pathology, which is initiated at the motor end-plate region, is evident as early as 30 minutes after paraoxon administration and is characterized by dilated mitochondria, expanded sarcoplasmic reticulum, fused and widened subsynaptic folds, and coated cleft vesicles. By 24 hours, a generalized breakdown of muscle fiber architecture is evident with an accompanying infiltration of phagocytes. Electrophysiological studies have shown that paraoxon increases neurotransmitter release and causes spontaneous and impulse-related antidromic nerve activity, both of which can be reduced significantly by reactivation of inhibited acetylcholinesterase (AChE) with pyridine-2-aldoxime methiodide. The severity of the myopathy has been found to be positively correlated to the degree and duration of AChE inhibition. It appears that 2 hours of inhibition, with a critical loss in activity, viz., 85%, is necessary to initiate severe muscle fiber necrosis. Prior nerve transection prevents myopathic development and current data support the hypothesis that the induction of skeletal muscle fiber necrosis is triggered by inhibition of a neurally regulated fraction of AChE.
Acetylcholine↗
Premeal insulin administration lowers postprandial blood glucose and increases myocardial microvascular blood flow in people with type 1 diabetes: a randomised, crossover clinical trial.
AIMS/HYPOTHESIS: We aimed to evaluate whether prandial insulin timing affects vascular function in people with type 1 diabetes. Our hypothesis was that premeal insulin administration would lead to greater myocardial microvascular blood flow (MBF) via blunting postprandial hyperglycaemia. METHODS: People with type 1 diabetes between 18 and 35 years of age with BMI <30 kg/m2 underwent two protocols with a 1:1 randomised crossover design wherein prandial insulin was injected either 15 min before or 15 min after meal intake began. To provide a physiological comparison, age-, sex- and BMI-matched control participants completed one study where they consumed the same meal but received no exogenous insulin. Glucose, insulin, vascular function (including ultrasound measures of myocardial and skeletal muscle microvascular perfusion, aortic stiffness, brachial artery endothelial function) and biomarkers of systemic inflammation and endothelial dysfunction were assessed at baseline and then 2 h after meal ingestion within each protocol. The primary outcome was change in myocardial MBF within each protocol. Study personnel assessing outcomes were masked to group assignment. RESULTS: Eighteen people with type 1 diabetes and 18 matched control participants were analysed within each protocol. Glucose area under the curve was significantly greater (p=0.015) in the postmeal insulin study compared with the premeal insulin study in participants with type 1 diabetes. Myocardial microvascular flow velocity significantly increased (p=0.031) with premeal insulin administration in people with type 1 diabetes and this consequently led to greater myocardial MBF (p=0.044). There were no changes in myocardial MBF within the other protocols. Changes in vital signs were similar between all protocols. CONCLUSIONS/INTERPRETATION: Appropriately timed premeal insulin led to lower postprandial blood glucose along with increased myocardial MBF in people with type 1 diabetes. Further work is needed to determine the underlying aetiology of these changes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04730882.
Humans↗
Integrated Multiomics Analyses of the Molecular Landscape of Sarcopenia in Alcohol-Related Liver Disease.
BACKGROUND: Skeletal muscle is a major target for ethanol-induced perturbations, leading to sarcopenia in alcohol-related liver disease (ALD). The complex interactions and pathways involved in adaptive and maladaptive responses to ethanol in skeletal muscle are not well understood. Unlike hypothesis-driven experiments, an integrated multiomics-experimental validation approach provides a comprehensive view of these interactions. METHODS: We performed multiomics analyses with experimental validation to identify novel regulatory mechanisms of sarcopenia in ALD. Studies were done in a comprehensive array of models including ethanol-treated (ET) murine and human-induced pluripotent stem cell-derived myotubes (hiPSCm), skeletal muscle from a mouse model of ALD (mALD) and human patients with alcohol-related cirrhosis and controls. We generated 13 untargeted datasets, including chromatin accessibility (assay for transposase accessible chromatin), RNA sequencing, proteomics, phosphoproteomics, acetylomics and metabolomics, and conducted integrated multiomics analyses using UpSet plots and feature extraction. Key findings were validated using immunoblots, redox measurements (NAD+/NADH ratio), imaging and senescence-associated molecular phenotype (SAMP) assays. Mechanistic studies included mitochondrial-targeted Lactobacillus brevis NADH oxidase (MitoLbNOX) to increase redox ratio and MitoTempo as a mitochondrial free radical scavenger. RESULTS: Multiomics analyses revealed enrichment in mitochondrial oxidative function, protein synthesis and senescence pathways consistent with the known effects of hypoxia-inducible factor 1α (HIF1α) during normoxia. Across preclinical and clinical models, HIF1α targets (n = 32 genes) and signalling genes (n > 100 genes) (n = 3 ATACseq, n = 65 phosphoproteomics, n = 10 acetylomics, n = 6 C2C12 proteomics, n = 106 C2C12 RNAseq, n = 64 hiPSC RNAseq, n = 30 hiPSC proteomics, n = 3 mouse proteomics, n = 25 mouse RNAseq, n = 8 human RNAseq, n = 3 human proteomics) were increased. Stabilization of HIF1α (C2C12, 6hEtOH 0.24 ± 0.09; p = 0.043; mALD 0.32 ± 0.074; p = 0.005; data shown as mean difference ± standard error mean) was accompanied by enrichment in the early transient and late change clusters, -log(p-value) = 1.5-3.8, of the HIF1α signalling pathway. Redox ratio was reduced in ET myotubes (C2C12: 15512 ± 872.1, p < 0.001) and mALD muscle, with decreased expression of electron transport chain components (CI-V, p < 0.05) and Sirt3 (C2C12: 0.067 ± 0.023, p = 0.025; mALD: 0.41 ± 0.12, p = 0.013). Acetylation of mitochondrial proteins was increased in both models (C2C12: 107364 ± 4558, p = 0.03; mALD: 40036 ± 18 987, p = 0.049). Ethanol-induced SAMP was observed across models (P16: C2C12: 0.2845 ± 0.1145, p < 0.05; hiPSCm: 0.2591, p = 0.041). MitoLbNOX treatment reversed redox imbalance, HIF1α stabilization, global acetylation and myostatin expression (p < 0.05). CONCLUSIONS: An integrated multiomics approach, combined with experimental validation, identifies HIF1α stabilization and accelerated post-mitotic senescence as novel mechanisms of sarcopenia in ALD. These findings show the complex molecular interactions leading to mitochondrial dysfunction and progressive sarcopenia in ALD.
Sarcopenia↗
PIEZO1 Mediates Myoblast Proliferation Under Simulated Microgravity.
Skeletal muscle atrophy is a major health risk of prolonged spaceflight, yet how microgravity reshapes muscle cells through mechanotransduction remains poorly understood. Here, we examined the mechanosensitive cation channel PIEZO1 in myoblast proliferation under simulated microgravity. Using a two-dimensional clinostat combined with Hi-C-based 3D genomics, transcriptomics, and functional assays, we found that simulated microgravity promotes C2C12 myoblast proliferation and upregulates Piezo1. Piezo1 mRNA knockdown reduced both proliferation and depolarization-induced Ca2 + influx, each partially restored under simulated microgravity, consistent with PIEZO1 being a central mediator of the response. Simulated microgravity also drove extensive 3D genome reorganization alongside changes in proliferation-related gene expression. Integrating chromatin architecture with transcriptomics, we found that PIEZO1 inhibition increased Elavl2 mRNA expression, PIEZO1 activation suppressed Elavl2 mRNA expression, and Elavl2 mRNA knockdown enhanced cell proliferation. These findings define a PIEZO1-ELAVL2 mechanotransduction axis, coupled to 3D chromatin remodeling, that regulates myoblast proliferation under simulated microgravity, and thus may be a target for countering spaceflight-associated muscle dysfunction.
Cell Proliferation↗
COVID-19 multi-omics reveal organ-specific responses and biomarkers.
OBJECTIVE: Post-COVID-19 syndrome is characterised by persistent immune dysfunction and multi-organ sequelae. This study aimed to characterise the systemic blood molecular landscape induced by SARS-CoV-2 infection and identify prognostic markers linked to skeletal muscle mass loss, a key driver of poor outcomes. METHODS: We enrolled 30 healthy controls and 307 COVID-19 patients, collecting 422 plasma samples for integrated proteomic and metabolomic profiling to investigate organ-specific molecular alterations in COVID-19. RESULTS: We comprehensively mapped the molecular landscape of COVID-19, encompassing immune, tissue-specific, and metabolic perturbations, and delineated their interactions. Focusing on organ-damage-related molecular patterns associated with disease progression and mortality, we found that skeletal muscle mass loss contributed to poor clinical outcomes of COVID-19 (p < 0.0001). Dysregulated arginine metabolism emerged as a key metabolic signature in fatal COVID-19 cases, with GLUL, GOT1, and citrulline showing significant correlation with skeletal muscle mass loss. Longitudinal analyses further revealed that reduced citrulline levels underlie the poor outcome of COVID-19 patients with muscle mass loss. These findings were robustly supported through multiple approaches: Mendelian randomization confirmed causal relationships between citrulline depletion, sarcopenia/fat-free mass loss, and COVID-19 mortality (p < 0.05), transcriptomic analyses of SARS-CoV-2-infected golden hamsters (GSE231910) provided additional support in enrichment of arginine biosynthesis (FDR < 0.05), and in vitro experiments further demonstrated that citrulline depletion promotes pro-inflammatory M1 macrophage polarisation — a key immunological feature of critical COVID-19. Leveraging these insights, we developed a skeletal muscle loss-specific prognostic prediction model for COVID-19 using GLUL, GOT1, and citrulline. This model effectively stratified patients into high- and low-risk groups (p = 0.035). CONCLUSION: Our study advances the understanding of COVID-19-induced organ pathophysiology and provides a foundation for developing targeted therapeutic strategies for post-COVID sequelae.
COVID-19↗
Neurologic manifestations in sarcoidosis: review of the literature, with a report of 23 cases.
Nervous system involvement by sarcoidosis has been considered rare, yet more than 400 cases have been reported. We present 23 additional cases here, including 14 with autopsies, and we review the literature. The overall frequency of neurologic involvement is 5%. Patients usually have other stigmata of sarcoidosis; however, neurologic dysfunction is frequently the presenting finding. The protean manifestations of central nervous system (CNS) involvement usually occur in the early phase of the disease, while those of peripheral nervous system and skeletal muscle involvement are characteristically seen in the chronic stages. Basal granulomatous meningitis causes most of the CNS manifestations either by infiltration or compression of adjacent structures. Steroids are the mainstay of therapy, and the overall response is quite variable. The course is also variable, being transient in some and chronic in others. The prognosis is better with peripheral than with central nervous system involvement.
Adolescent↗