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PubMed1976

Iron deficiency in the rat. Physiological and biochemical studies of muscle dysfunction.

Work performance on a treadmill has been evaluated in normal and iron-deficient rats. Anemia was removed as a variable by adjusting the hemoglobin of all animals to the same concentration. At a hemoglobin compatible with normal work performance, iron-deficient animals showed a marked impairment of running ability as compared to control animals. Iron therapy corrected the disability within 4 days. Concentrations of the cytochrome pigments and myoglobin, and rates of oxidative phosphorylation with pyruvate-malate, succinate, and alpha-glycerophosphate as substrates were all reduced in mitochondrial preparations from skeletal muscle of iron-deficient rats, but only the rate of phosphorylation with alpha-glycerophosphate as substrate increased significantly and in parallel with the recovery in work performance of the iron-deficient rats treated with iron dextran.

Anemia, Hypochromic↗
PubMed1979

Radiography of glycogen storage diseases.

Sixty-three patients with glycogen storage disease were evaluated. Findings on plain film examinations, excretory urography, barium gastrointestinal studies, ultrasonography, and angiography were categorized by type of glycogen storage disease. In type I findings include hepatomegaly with hepatic dysfunction, renomegaly with an increased incidence of renal calculi, and osteopenia with various associated osseous abnormalities. These changes were less pronounced in types III, IV, and VI. Type II displayed either cardiac or skeletal muscle glycogen deposition. Correlation with postmortem examination in 14 individuals is given.

Adolescent↗
PubMed1975

The syndrome of systemic carnitine deficiency. Clinical, morphologic, biochemical, and pathophysiologic features.

An 11-year old boy had had recurrent episodes of hepatic and cerebral dysfunction and underdeveloped musculature. Overt weakness developed at age 10. Lipid excess, especially in type I fibers, was found in muscle. Hypertrophied smooth endoplasmic reticulum and excessive microbodies were present in liver. Marked carnitine deficiency was shown in skeletal muscle, plasma, and liver. Ketogenesis was impaired on a high fat diet, but omega oxidation of fatty acids was enhanced. There was excessive glucose uptake and essentially no oxidation of labeled long-chain fatty acids by perfused forearm muscles in vivo. Oral replacement therapy restored plasma carnitine levels to normal, but not liver or muscle carnitine levels, and was accompanied by clinical improvement.

Adenosine Triphosphatases↗
PubMed1977

The effect of bite plane use on terminal hinge axis location.

The effect of bite phase therapy on the location of hinge axis was observed and compared in a sample of normal subjects and a group of individuals with TMJ dysfunction. The normal group displayed a mean change of 1.0 mm with a range of 0.3 mm to 3.4 mm between bite plane use and its absence. The direction of change with bite plane use was anterior with a tendency for superior component. The same group utilized the bite plane a second time and the axis location was compared with the original determined with bite plane use. This procedure was done to test the reproducibility of hinge axis on normal subjects. The mean change between the two bite plane uses was .87 mm with a range of 0.0 mm to 3.0 mm. The symptomatic patients changed a mean of 1.46 mm with a range of 0.0 to 3.3 mm. The direction of change was definitely posterior following therapy with a strong tendency for a superior component. This study seems to emphasize the need for a relaxed and asymptomatic muscular pattern for individuals on whom occlusal adjustments are to be made. In the presence of erroneous maxillomandibular skeletal relationships inaccuracy is inherent for occlusal equilibration.

Adolescent↗
PubMed2026

Proteins as Regulators of Metabolic Changes in Sepsis: Alterations in Body Fluids, Immune Cells, and Organs through the Eyes of Proteomics.

Sepsis is a life-threatening syndrome characterized by a dysregulated host response to infection and profound metabolic alterations that contribute to immune dysfunction and organ failure. This Review synthesizes proteomic evidence on sepsis-associated alterations in proteins involved in metabolic pathways across circulating biofluids, immune cells, and organs. Across plasma and urine, proteomic studies identify disturbances in lipoprotein-associated pathways, redox homeostasis, mitochondrial function, and substrate metabolism, indicating that protein signatures of metabolic dysregulation are systemic and detectable across biofluids. In immune cells, monocytes and neutrophils, proteomic analyses reveal a shift toward glycolysis with concurrent impairment of mitochondrial pathways alongside phenotype-dependent differences in lipid and redox-related programs. Organ-level studies further show that metabolic responses are heterogeneous, with distinct trajectories in the kidney, heart, liver, lung, skeletal muscle, and brain. These observations support the concept that sepsis involves compartment-specific remodeling of metabolism-associated protein networks rather than a single convergent metabolic state. Proteomics also highlights potential translational opportunities by identifying metabolism-associated proteins linked to disease severity, clinical phenotypes, and biologically distinct patient subgroups, although the current evidence remains largely exploratory and context-dependent. Overall, proteomics provides a complementary framework for understanding the molecular regulation of sepsis-associated metabolic dysfunction and may refine biological stratification and therapeutic targeting, particularly when integrated with longitudinal sampling and multiomic data.

Humans↗
PubMed2026

Impaired stem cell migration and divisions in Duchenne muscular dystrophy revealed by live imaging.

Dysregulation of stem cell properties is a hallmark of many pathologies, but the dynamic behaviour of stem cells in their microenvironment during disease progression remains poorly understood. Using the mdx mouse model of Duchenne Muscular Dystrophy, we developed innovative live imaging of muscle stem cells (MuSCs) in vivo, and ex vivo on isolated myofibres. We show that mdx MuSCs have impaired migration and precocious differentiation through unbalanced symmetric divisions, driven by p38 and PI3K signalling pathways, in contrast to the p38-only dependence of healthy MuSCs. Cross-grafting shows that MuSC fate decisions are governed by fibre-independent cues, whereas their migration behaviour is determined by the myofibre niche. This study provides the first dynamic analysis of dystrophic MuSC properties in vivo, reconciling conflicting reports on their function. Our findings establish DMD as a MuSC disease with niche dysfunctions, offering strategies to restore stem cell functions for improved muscle regeneration.

Stem Cells↗
PubMed1979

Lactate elimination in man: effects of lactate concentration and hepatic dysfunction.

Lactate elimination was studied in twenty-six healthy volunteers during primed constant lactate infusion or multiple lactate injection tests, at blood lactate concentrations of 1-8 mmol-1. Although lactate elimination fitted a single exponential curve over a 30 min period, a significant correlation between the rate removal constant (KL) and the peak blood lactate concentration (Lphi) was demonstrated: loge KL = -2.43-0.132 Lphi (P = 0.003, r = 0.63, n = 20) This suggests that lactate removal does not follow first order kinetics over a wide concentration range but becomes saturated at relatively low blood lactate concentrations. Estimates of the lactate distribution volume did not differ significantly at different dosage levels, but remained in the range 270-300 ml kg-1. Skeletal muscle uptake accounted for about 26% of the infused lactate load. Seven patients with well-compensated hepatic cirrhosis were compared with a group of six control subjects during primed constant infusion tests. Fasting and steady state blood lactate concentrations achieved were similar in both groups. A significant prolongation in lactate half-life was demonstrated in the cirrhotics (18.8 +/- 1.4 min (mean +/- SEM) compared to 14.7 +/- 2.2 min; P less than 0.02). Since peripheral uptake of lactate in the forearm was similar in the two groups, this suggests that hepatic lactate uptake was impaired, due either to hepatocyte dysfunction or portal diversion.

Adult↗
PubMed2024

The effect of low birth weight as an intrauterine exposure on the early onset of sarcopenia through possible molecular pathways.

Sarcopenia, a musculoskeletal disease characterized by the progressive loss of skeletal muscle mass, strength, and physical performance, presents significant challenges to global public health due to its adverse effects on mobility, morbidity, mortality, and healthcare costs. This comprehensive review explores the intricate connections between sarcopenia and low birth weight (LBW), emphasizing the developmental origins of health and disease (DOHaD) hypothesis, inflammatory processes (inflammaging), mitochondrial dysfunction, circadian rhythm disruptions, epigenetic mechanisms, and genetic variations revealed through genome-wide studies (GWAS). A systematic search strategy was developed using PubMed to identify relevant English-language publications on sarcopenia, LBW, DOHaD, inflammaging, mitochondrial dysfunction, circadian disruption, epigenetic mechanisms, and GWAS. The publications consist of 46.2% reviews, 21.2% cohort studies, 4.8% systematic reviews, 1.9% cross-sectional studies, 13.4% animal studies, 4.8% genome-wide studies, 5.8% epigenome-wide studies, and 1.9% book chapters. The review identified key factors contributing to sarcopenia development, including the DOHaD hypothesis, LBW impact on muscle mass, inflammaging, mitochondrial dysfunction, the influence of clock genes, the role of epigenetic mechanisms, and genetic variations revealed through GWAS. The DOHaD theory suggests that LBW induces epigenetic alterations during foetal development, impacting long-term health outcomes, including the early onset of sarcopenia. LBW correlates with reduced muscle mass, grip strength, and lean body mass in adulthood, increasing the risk of sarcopenia. Chronic inflammation (inflammaging) and mitochondrial dysfunction contribute to sarcopenia, with LBW linked to increased oxidative stress and dysfunction. Disrupted circadian rhythms, regulated by genes such as BMAL1 and CLOCK, are associated with both LBW and sarcopenia, impacting lipid metabolism, muscle mass, and the ageing process. Early-life exposures, including LBW, induce epigenetic modifications like DNA methylation (DNAm) and histone changes, playing a pivotal role in sarcopenia development. Genome-wide studies have identified candidate genes and variants associated with lean body mass, muscle weakness, and sarcopenia, providing insights into genetic factors contributing to the disorder. LBW emerges as a potential early predictor of sarcopenia development, reflecting the impact of intrauterine exposures on long-term health outcomes. Understanding the complex interplay between LBW with inflammaging, mitochondrial dysfunction, circadian disruption, and epigenetic factors is essential for elucidating the pathogenesis of sarcopenia and developing targeted interventions. Future research on GWAS and the underlying mechanisms of LBW-associated sarcopenia is warranted to inform preventive strategies and improve public health outcomes.

Humans↗
PubMed1975

Cellular potassium transport and ATPase activity in Bartter's syndrome.

The cellular membrane function expressed as ATPase activity and active cellular K+ changes during in vitro incubation has been studied in two siblings with Bartter's syndrome. The K+ content of skeletal muscle was 20% lower than for controls, and the active potassium transport ability of single skeletal muscle cells was also lower than that of controls. The total ATPase activity of red cell membranes was higher, but the ratio of Na+-K+-activated to Mg2+-activated ATPases was lower than for control patients. The results favour the hypothesis that a primary defect causing the Bartter's syndrome could be an inherited generalized membrane dysfunction in the handling of cations.

Adenosine Triphosphatases↗
PubMed1978

Modern urodynamic evaluations in the urologist's office.

Patients with voiding disturbances comprise 20 per cent of the yearly outpatient visits to urologists. Of this number 25 per cent have significant neurogenic bladder dysfunction. The theoretical basis and experimental demonstration of urodynamics have been established and reported by multiple investigators during the last 15 years. Recent advances in clinical applications of fast-flow gas cystometry have led to the development of complete, portable urodynamic units that can be used conveniently in the urologist's office and are capable of simultaneously recording parameters of detrusor, urethral and skeletal muscle phincter function. This equipment is simple, efficient, economical and can be operated by well trained paramedical personnel, with minimal immediate direction required by a physician. With recent recognition by many third party carriers this equipment may amortize itself rapidly but, more importantly, it may serve to identify neurological diseases of the bladder that are undetected by other conventional methods of investigation. During the last 9 months 213 patients have undergone urodynamic evaluation at our outpatient urology clinic. These patients were categorized according to type and incidence of voiding disturbance and the number of neurogenic bladders diagnosed within each group was compiled and discussed. Several of the more interesting and unusual clinical examples are presented to familiarize the urologist with the interpretative aspects of this study.

Ambulatory Care↗
PubMed1977

Ethanolaminosis. A newly recognized, generalized storage disease with cardiomegaly, cerebral dysfunction and early death.

A storage disease with cardiomegaly, generalized muscular hypotonia, cerebral dysfunction, failure to thrive and early death is described in two siblings. The first one died at the age of 10 months, the second at the age of 17 months. The symptoms were mainly due to lysosomal storage of a substance which had a positive reaction to PAS and Best's stain and which was resistant to diastase. This substance was stored in nearly all the organs, especially in the heart, liver, spleen and less in the brain and skeletal muscles. An increased renal excretion of ethanolamine, a greatly increased hepatic concentration of ethanolamine and diminished hepatic ethanolamine kinase activity could be demonstrated. Ethanolamine is essential for the synthesis of phospholipids. Both parents showed increased renal excretion of taurine. In several aspects, this syndrome is similar to the glycogenosis type II described by Pompe.

Brain Chemistry↗
PubMed1979

Recurrent hypoglycemia associated with glutaric aciduria type II in an adult.

Repeated episodes of hypoglycemia accompanied by elevated serum concentrations of free fatty acid without ketosis, fatty infiltration of the liver, hepatic dysfunction, and proximal myopathy in a 19-year-old woman, prompted us to analyze her urine for organic acids. Greatly increased quantities of glutaric acid, ethylmalonic acid, dicarboxylic acids with six to 10 carbons, and isovalerylglycine were consistently found in her urine. The ability of cultured skin fibroblasts from the patient to oxidize [1(-14)C]butyrate and [2(-14)C]lysine was reduced. These urinary and in vitro findings indicated defective activity of several acyl coenzyme A dehydrogenases, including glutaryl, isovaleryl, and butyryl coenzyme A dehydrogenases -- establishing a diagnosis of glutaric aciduria Type II. Carnitine concentrations in the skeletal muscle and liver were moderately reduced, but carnitine deficiency was considered a secondary biochemical abnormality. Although glutaric aciduria Type II has previously been described only in a neonate, the disease must be considered in the differential diagnosis of hypoglycemia in adults.

Adult↗
PubMed1978

Sequence of cardiac changes in Duchenne muscular dystrophy.

Boys with Duchenne muscular dystrophy (DMD) rarely have clinical evidence of myocardial dysfunction during life. Nevertheless, congestive heart failure is a frequent terminal event and autopsy invariably shows dystrophic myocardial involvement. Little is known regarding the progression of heart functional abnormalities in boys with DMD from birth to death. Therefore we have examined the hearts of 18 DMD boys aged 4 to 15 years with the following non-invasive methods: cardiovascular physical examination, electrocardiography, chest x-ray, serum enzymes, and echocardiography. Control subjects were 25 normal boys matched to their DMD counterparts by age and by body surface area. The dystrophic patients were divided into early (N = 9) and late (N = 9) DMD according to manual muscle testing of skeletal muscles. In early DMD, six of 23 cardiac indices differed from control boys; in the late stage, an additional five indices became abnormal. Early DMD was characterized by these abnormalities: tachycardia, large ECG R/S ratio in V1, augmented q wave voltages in Leads I, II, and V5 of the ECG, diminished contractile excursion of the left venticular posterior wall (LVPW) and interventricular septum, and decreased rate of relaxation of the LVPW. In late DMD additional cardiac abnormalities appeared: enlarged heart volume by x-ray, reduced cardiac ejection fraction, diminished change in left ventricular diameter from diastole to systole, reduced maximal systolic endocardial velocity, and decreased rate of circumferential fiber shortening as detected in the echocardiogram. Most of the cardiac abnormalities were revealed only by echocardiography, which is thus shown to be a sensitive method for monitoring the progression of cardiac dystrophy during the life span of the DMD child.

Adolescent↗
PubMedDate not supplied

Serum cardiac enzymes in stroke.

Serum cardiac enzyme levels (CK, LDH, SGOT) were estimated and the ECG recorded for 4 days following admission of 288 patients (Group I) to a stroke intensive care unit. Sixty-four of these patients, subsequently found not to have strokes, served as controls. Mean serum levels of all 3 cardiac enzymes were elevated in 8% of the 224 patients with stroke. The mean serum enzyme levels in patients with transient ischemic attacks (TIA) did not differ from controls. In a second group of 230 patients with stroke (Group II) serum CK levels were measured and the isoenzyems were fractionated to determine the tissue source of the enzymes. One hundred and one patients had raised total CK values and 25 of these (11%) had raised CK-MB (heart) iso-enzyme, the remainder having CK-MM (skeletal muscle) fraction. No serum CK-BB (brain) iso-enzyme was detected in any patient. Patients with positive serum levels of CK-MB has more evidence of acute myocardial ischemia on ECG (p less than 0.05), and more cardiac arrhythmias (p less than 0.001) than those with normal CK levels. Scattered areas of myocytolysis were found in the myocardium at autopsy in one patient. The acute rise in serum cardiac enzymes which we have recorded in the initial stages of stroke suggest that acute myocardial involvement is a commoner complication than is generally recognized. Also, since the CK-MB rises were modest and progressive, it is more likely that this acute myocardial dysfunction is a consequence, rather than a cause, of the acute cerebrovascular lesion.

Arrhythmias, Cardiac↗
PubMed1976

Parkinsonism and neurogenic bladder. Experimental and clinical observations.

In a group of patients suffering from Parkinson's disease, beside neurogenic bladder dysfunction, we have also found dysfunction affecting the external sphincter musculature. Treatment with L-Dopa probably improves the urethral symptoms by providing a relaxing effect on the urethral closure pressur together with better coordination of the pelvic floor and external sphincter Mechanism during micturition. The effect was parallel to the improvement in Parkinsonion symptoms. Experimental studies demonstrate the ability of L-Dopa to reduce urethral closure pressure and this effect was related to a central effect on the skeletal musculature.

Animals↗
PubMed2026

Efficacy and Safety of Bimagrumab in Adults With Obesity and Metabolic Dysfunction: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

AIMS: This study aims to systematically evaluate the efficacy of bimagrumab on body composition and glucose parameters in adults with obesity and metabolic dysfunction and its safety profile. METHODS: We searched MEDLINE, PubMed, Embase, and the Cochrane Library on April 20, 2026, for randomized controlled trials (RCTs) assessing bimagrumab treatment in adults with obesity, insulin resistance, or type 2 diabetes mellitus (T2DM). The risk of bias was assessed using the Cochrane Risk of Bias tool (RoB 2), and meta-analyses of efficacy and safety data were conducted using R software. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system was used to assess the strength of evidence. The study was registered with PROSPERO (CRD420261377110). RESULTS: Of the 134 retrieved records, 4 RCTs (enrolling 268 participants) were included. The included population represented a broad spectrum of metabolic dysfunction, from obesity and nondiabetic insulin resistance to established T2DM. Compared with placebo, bimagrumab treatment significantly reduced total weight (mean difference [MD] -4.85 kg, 95% confidence interval [CI] -6.82 to -2.88), fat mass (-4.72 kg [-8.05 to -1.40]), and glycated haemoglobin (HbA1c) (-0.13% [-0.23 to -0.03]) and significantly increased total lean mass (1.66 kg [0.81 to 2.51]). However, bimagrumab led to an increase in low-density lipoprotein (LDL) concentrations of 0.47 mmol/L [0.03 to 0.91] and significantly increased incidences of discontinuation (risk ratio [RR] 5.75 [1.61 to 20.46]), muscle spasms (RR 10.44 [4.23 to 25.75]), and diarrhoea (RR 4.91 [2.38 to 10.11]). CONCLUSION: Bimagrumab effectively reversed adverse effects on body composition in obese individuals, resulting in significant fat reduction, increased skeletal muscle mass, and improved glycemic control, suggesting that bimagrumab is a promising new target for personalized metabolic therapy.

Humans↗
PubMed2026

A mouse model of autosomal dominant spastic ataxia and myopathy caused by a mutation in Tuba4a.

Hereditary ataxias are a heterogeneous group of neurodegenerative disorders characterized by impaired balance and coordination, often due to cerebellar dysfunction. Despite advances in identifying genetic causes, animal models remain essential for dissecting underlying mechanisms and testing therapeutic strategies. Here we describe a mouse model of spastic ataxia and myopathy caused by a missense mutation in Tuba4a (n.A626C, p.Gln176Pro). In an ENU mutagenesis screen, a male C57BL/6 J mouse exhibiting muscle wasting and an intention tremor starting at approximately 4 weeks-of-age was identified. The male was bred by in vitro fertilization to BALB/cByJ oocyte donors. Genetic mapping determined dominant inheritance and localized the mutation to Chromosome 1. Genome sequencing revealed single nucleotide polymorphisms (SNPs) in serine threonine kinase 36 (Stk36Y1003N) and alpha-tubulin 4A (Tuba4aQ176P) in the mapping interval. These SNPs were CRISPR-engineered into C57BL/6 J mice, which confirmed the Tuba4aQ176P variant as the causative mutation. Mutant mice are normal at 3 weeks, except for decrement in muscle response following repetitive nerve stimulation. However, by 30 days these mice have overt ataxia, Purkinje neuron degeneration, and extensive skeletal muscle defects, which contribute to a decreased lifespan. Dominant TUBA4A mutations in humans are associated with spastic ataxia type 11 (SPAX11), congenital myopathy type 26 (CMYO26), and frontotemporal dementia/amyotrophic lateral sclerosis type 9 (FTDALS9). Our mice exhibit hallmark features of SPAX11 and CMYO26, but do not show motor neuron degeneration. This specificity makes this model a valuable tool for studying cell-type selective effects of TUBA4A mutations in neurodegeneration and myopathy.

Animals↗
PubMed2025

Granulopoietic Dysregulation in a Patient-Tailored Mouse Model of Barth Syndrome.

Barth syndrome (BTHS) is an X-linked recessive disorder characterized by cardiomyopathy, skeletal muscle myopathy and fatigue, growth restriction, and neutropenia. Neutropenia increases the risk of life-threatening bacterial infections, a major cause of death in individuals with BTHS. Currently, there is no curative treatment for BTHS or associated neutropenia. The development of therapeutic strategies to correct BTHS-associated neutropenia has been hindered by a limited understanding of the underlying molecular mechanisms involved. BTHS is caused by a mutation in the Tafazzin gene encoding a transacylase required for the maturation of cardiolipin, an inner mitochondrial membrane phospholipid crucial for mitochondrial structure and function. We introduced a BTHS patient's point mutation (TAZD75H) into the mouse Tafazzin enzyme's critical acyltransferase site using CRISPR/Cas9-mediated genome editing, resulting in a patient-tailored point mutant knock-in BTHS model (TazD75H) that expresses a stable mutant TazD75H protein lacking transacylase activity. TazD75H mice were then used to investigate how loss of Tafazzin enzymatic activity impacts hematopoiesis. Male TazD75H mice exhibited impaired granulopoiesis and neutropenia secondary to impaired function of hematopoietic progenitors. Furthermore, they demonstrated age-dependent neutrophil maturation impairment reflecting the variable neutropenia observed in BTHS patients. Additionally, male TazD75H mice exhibit chronic lymphopenia that persists post TazD75H bone marrow transplantation. Mechanistically, the TAZD75H point mutation caused hematopoietic cell mitochondrial dysfunction in patient-derived immortalized TAZD75H lymphoblasts, increasing reactive oxygen species production and mitochondrial membrane depolarization. Likewise, Cyclosporine A treatment rescued these mitochondrial phenotypes in vitro, confirming TAZD75H mitochondrial dysfunction. Overall, our findings demonstrate that mitochondrial dysfunction secondary to TAFAZZIN loss of enzymatic function underlies BTHS-associated neutropenia and lymphopenia.

Animals↗