Skeletal Muscle Manifestations Research Articles

Cardiac and skeletal muscle manifestations in the G608G mouse model of Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder resulting from de novo mutations in the lamin A gene. Children with HGPS typically pass away in their teenage years due to cardiovascular diseases such as atherosclerosis, myocardial infarction, heart failure, and stroke. In this study, we characterized the G608G HGPS mouse model and explored cardiac and skeletal muscle function, along with senescence-associated phenotypes in fibroblasts. Homozygous G608G HGPS mice exhibited cardiac dysfunction, including decreased cardiac output and stroke volume, and impaired left ventricle relaxation. Additionally, skeletal muscle exhibited decreased isometric tetanic torque, muscle atrophy, and increased fibrosis. HGPS fibroblasts showed nuclear abnormalities, decreased proliferation, and increased expression of senescence markers. These findings provide insights into the pathophysiology of the G608G HGPS mouse model and inform potential therapeutic strategies for HGPS.

Mitochondrial myopathies diagnosed in adulthood: clinico-genetic spectrum and long-term outcomes.

Mitochondrial myopathies are frequently recognized in childhood as part of a broader multisystem disorder and often overlooked in adulthood. Herein, we describe the phenotypic and genotypic spectrum and long-term outcomes of mitochondrial myopathies diagnosed in adulthood, focusing on neuromuscular features, electrodiagnostic and myopathological findings and survival. We performed a retrospective chart review of adult patients diagnosed with mitochondrial myopathy at Mayo Clinic (2005-21). We identified 94 patients. Median time from symptom onset to diagnosis was 11 years (interquartile range 4-21 years). Median age at diagnosis was 48 years (32-63 years). Primary genetic defects were identified in mitochondrial DNA in 48 patients (10 with single large deletion, 38 with point mutations) and nuclear DNA in 29. Five patients had multiple mitochondrial DNA deletions or depletion without nuclear DNA variants. Twelve patients had histopathological features of mitochondrial myopathy without molecular diagnosis. The most common phenotypes included multisystem disorder (n = 30); mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (14); limb myopathy (13); chronic progressive external ophthalmoplegia (12); and chronic progressive external ophthalmoplegia-plus (12). Isolated skeletal muscle manifestations occurred in 27%. Sixty-nine per cent had CNS and 21% had cardiac involvement. Mutations most frequently involved MT-TL1 (27) and POLG (17); however, a wide spectrum of established and novel molecular defects, with overlapping phenotypes, was identified. Electrodiagnostic studies identified myopathy (77%), fibrillation potentials (27%) and axonal peripheral neuropathy (42%, most common with nuclear DNA variants). Among 42 muscle biopsies available, median percentage counts were highest for cytochrome C oxidase negative fibres (5.1%) then ragged blue (1.4%) and ragged red fibres (0.5%). Skeletal muscle weakness was mild and slowly progressive (decline in strength summated score of 0.01/year). Median time to gait assistance was 5.5 years from diagnosis and 17 years from symptom onset. Thirty patients died, with median survival of 33.4 years from symptom onset and 10.9 years from diagnosis. Median age at death was 55 years. Cardiac involvement was associated with increased mortality [hazard ratio 2.36 (1.05, 5.29)]. There was no difference in survival based on genotype or phenotype. Despite the wide phenotypic and genotypic spectrum, mitochondrial myopathies in adults share similar features with slowly progressive limb weakness, contrasting with common multiorgan involvement and high mortality.

Examining the frequency of musculoskeletal manifestations in patients with thyroid dysfunction

Thyroid disorders affect body organs. This study was conducted aiming to examine the frequency of skeletal muscle manifestations in patients with thyroid dysfunction. This descriptive study's statistical population comprised 200 patients with thyroid disorders referred to the endocrinology clinic of Rafsanjan University of Medical Sciences from March 21, 2018, to September 23, 2018, who were included in the study by the census method. The research checklist included information from the complete physical evaluation of each patient's organs and demographic characteristics. Chi-square and Fisher's exact tests were used to analyze the data. The mean age of the examined patients was 39.25 ± 14.43 years. Of the 200 patients, 23 (11.5%) were male and 177 (88.5%) were female. Joint pain was found in 121 people (60.5%), morning stiffness in 45 people (22.5%), limited joint mobility in 44 people (22.0%), adhesive capsulitis in 25 people (12.5%), carpal tunnel syndrome in 24 people (0.12%), trigger finger disorder in 20 people (10.0%), and two patients (1.0%) experienced tarsal tunnel. No musculoskeletal manifestations were reported in 74 individuals (0.37%) with thyroid disorders. There was a significant relationship between musculoskeletal manifestations accompanying thyroid disorders and gender (P = 0.001), level of education (P < 0.001), and occupation (P = 0.002). The findings of this study indicated the comorbidity of musculoskeletal disorders and thyroid dysfunction. Therefore, patients with thyroid dysfunction should be screened for musculoskeletal complaints and, if necessary, receive appropriate treatment.

COVID-19 AND ITS RELATION TO ANOSMIA, AGEUSIA AND OTHER NEUROLOGICAL MANIFESTATIONS

Background: Coronavirus disease (COVID-19) is an infectious disease and highly contagious caused by a newly discovered coronavirus (SARS-CoV-2),was firstly reported in Wuhan. SARS-CoV-2belongs to the family Coronaviridae, which belongs to the order Nidovirales. It has be report that bats are the primary natural reservoir that houses a number of CoVs. Risk Factors include: Age, Gender, Diabetes, Hypertension, Cardiovascular Diseases, Malignancy.
 The Aim: of this study to review the impact this virus has on the nervous system. And to explore the neurological manifestations experienced by coronavirus disease (COVID-19) patients.
 Methods: The study was a review article. Data was collected during the period from 1– 29 September, 2021. PubMed and EBSCO Information Services were chosen as the search databases for the publications used within the study. Topics concerning the updates in types, management, and outcomes the neurological manifestations of Covid-19 cases, published in English around the world. No software was utilized to analyze the data. The data was extracted based on our specific objectives.
 Results: Myalgia, headache, altered sensorium, hyposmia, and hypogeusia were the most commonly reported neurological signs of COVID-19. COVID-19 can also cause ischemic stroke, intracerebral hemorrhage, encephalomyelitis, and acute myelitis in the central nervous system, as well as peripheral nervous system manifestations like Guillain-Barré syndrome and Bell's palsy and skeletal muscle manifestations like rhabdomyolysis in the peripheral nervous system.
 Conclusion: We conclude that neurological manifestations includingischemic strokes, hypogeusia, hyposmia represents the most evident neurological manifestations in COVID-19 patients.

Skeletal Muscle Manifestations and Creatine Kinase in COVID-19.

Background and PurposeSkeletal muscle symptoms and elevated creatine kinase (CK) levels have been consistently reported as part of the COVID-19 disease process. Previous studies have yet to show a consistent relationship between CK levels and skeletal muscle symptoms, disease severity, and death from COVID-19. The purpose of this study is to determine whether elevated CK is associated with a COVID-19 course requiring intubation, intensive care, and/or causing death. Secondary objectives: To determine if there is a relationship between elevated CK and (1) skeletal muscle symptoms/signs (2) complications of COVID-19 and (3) other diagnostic laboratory values.MethodsThis is a retrospective, single center cohort study. Data were collected from March 13, 2020, to May 13, 2020. This study included 289 hospitalized patients with laboratory-confirmed SARS-CoV-2 and measured CK levels during admission.ResultsOf 289 patients (mean age 68.5 [SD 13.8] years, 145 [50.2%] were men, 262 [90.7%] were African American) with COVID-19, 52 (18.0%) reported myalgia, 92 (31.8%) reported subjective weakness, and 132 (45.7%) had elevated CK levels (defined as greater than 220 U/L). Elevated CK was found to be associated with severity of disease, even when adjusting for inflammatory marker C-reactive protein (initial CK: OR 1.006 [95% CI: 1.002-1.011]; peak CK: OR 1.006 [95% CI: 1.002-1.01]; last CK: 1.009 [95% CI: 1.002-1.016]; q = .04). Creatine kinase was not found to be associated with skeletal muscle symptoms/signs or with other laboratory markers.ConclusionsCreatine kinase is of possible clinical significance and may be used as an additional data point in predicting the trajectory of the COVID-19 disease process.

Skeletal muscles and Covid-19: a systematic review of rhabdomyolysis and myositis in SARS-CoV-2 infection.

Myalgia is a widely publicised feature of Covid-19, but severe muscle injury can occur. This systematic review summarises relevant evidence for skeletal muscle involvement in Covid-19. A systematic search of OVID and Medline databases was conducted on 16/3/2021 and updated on 28/10/2021 to identify case reports or observational studies relating to skeletal muscle manifestations of Covid-19 (PROSPERO: CRD42020198637). Data from rhabdomyolysis case reports were combined and summary descriptive statistics calculated. Data relating to other manifestations were analysed for narrative review. 1920 articles were identified. From these, 61 case reports/series met inclusion criteria, covering 86 rhabdomyolysis cases. Median age of rhabdomyolysis patients was 50 years, (range 6-89). 49% had either hypertension, diabetes mellitus or obesity. 77% were male. Symptoms included myalgia (74%), fever (69%), cough (59%), dyspnoea (68%). Median peak CK was 15,783U/L. 28% required intravenous haemofiltration and 36% underwent mechanical ventilation. 62% recovered to discharge and 30% died. Dyspnoea, elevated CRP and need for intravenous haemofiltration increased risk of fatal outcome. Additional articles relating to skeletal muscular pathologies include 6 possible concomitant diagnoses or relapses of idiopathic inflammatory myopathies and 10 reports of viral-induced muscle injuries without rhabdomyolysis. Localised myositis and rhabdomyolysis with SARS-CoV-2 vaccination have been reported. Rhabdomyolysis is an infrequent but important complication of Covid-19. Increased mortality was associated with a high CRP, renal replacement therapy and dyspnoea. The idiopathic inflammatory myopathies (IIM) may have viral environmental triggers. However, to date the limited number of case reports do not confirm an association with Covid-19.

Neurological manifestations of COVID-19: a systematic review

IntroductionSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the global spread of coronavirus disease (COVID-19). Our understanding of the impact this virus has on the nervous system is limited. Our review aims to inform and improve decision-making among the physicians treating COVID-19 by presenting a systematic analysis of the neurological manifestations experienced within these patients.MethodsAny study, released prior to May 20, 2020, that reported neurological manifestations in patients infected by SARS-CoV-2 was systematically reviewed using the PRISMA (Preferred Reporting Items for Systemic review and Meta-Analysis) statement.ResultsOur systematic review included data from 37 articles: twelve retrospective studies, two prospective studies, and the rest case reports/series. The most commonly reported neurological manifestations of COVID-19 were myalgia, headache, altered sensorium, hyposmia, and hypogeusia. Uncommonly, COVID-19 can also present with central nervous system manifestations such as ischemic stroke, intracerebral hemorrhage, encephalo-myelitis, and acute myelitis, peripheral nervous manifestations such as Guillain-Barré syndrome and Bell’s palsy, and skeletal muscle manifestations such as rhabdomyolysis.ConclusionWhile COVID-19 typically presents as a self-limiting respiratory disease, it has been reported in up to 20% of patients to progress to severe illness with multi-organ involvement. The neurological manifestations of COVID-19 are not uncommon, but our study found most resolve with treatment of the underlying infection. Although the timeliness of this review engages current challenges posed by the COVID-19 pandemic, readers must not ignore the limitations and biases intrinsic to an early investigation.

CNS and COVID-19: Neurological symptoms of hospitalized patients with coronavirus in Iraq: A surveying case sequences study

Background: At the end of the year 2019 and exactly in December, several unsolved pneumonia suitcases happened in Wuhan, China and has quickly feast to further shares of the Chinese area, formerly to (EU, USA, and Asia). The outburst was established designate affected by a novel coronavirus. Aim of the study: to determine neurological symptoms of patients suffering from COVID-19. Patients and Methods: One hundred and seven patients attended to the research laboratory established severe acute respiratory syndrome from coronavirus infection. Information we remembered from 30 January 2020 to 21 March 26, 2020. Medical information was taken from electrical medicinal archives and studied by a skilled group of medical doctors. Neurological indicators descent into three groups: (1) diseases of the central nervous system (headache; dizziness; acute cerebrovascular disease; impaired consciousness; ataxia; and epilepsy) (2) signs and symptoms of the Peripheral nervous system (hypogeusia; hyposmia; hypoplasia; and neuralgia) (3) And symptoms of skeletal muscles. The neurologists were rechecked all Information of all neurological symptoms. Results: 107 patients deliberate, 44 (41.10%) were severe and 63 (58.90%) were mild patients. Matched with mild and severe patients were elder (58.70±15.00 years vs 48.90±14.70 years),had extra fundamental illnesses (42 [47.70%] vs 41 [32.50%]), particularly HTN (16 [36.40%] vs 9 [15.10%]), and exhibited a smaller amount characteristic indicators for example fever (20[45.50%] vs 46 [73.0%]) and cough (15[34.10%] vs 38 [61.10%]). Thirty-nine (36.40%) patients with symptoms of neurologic appearance. Additionally, severe patients with neurologic manifestations (20 [45.50%] vs 19 [30.20%]), for example CVA illness (3[5.70%] vs 1 [0.80%]), diminished awareness (6 [14.80%] vs 1[2.40%]) and injury of skeletal muscle (8[19.30%] vs 3[4.80%]). Conclusion: Matched with mild patients suffering from coronavirus; severe patients had neurologic manifestation established as acute CVA, awareness diminishing, and skeletal muscle manifestations.

Potential for the Use of Adamantanes for the Prevention and Treatment of the Neurological Complications of COVID-19

Widespread damage to the central and peripheral nervous systems resulting from COVID-19 is becoming well established. Features include impairments of the level [somnolence, stupor, coma] and content [confusion, delirium] of consciousness, impaired senses of taste, smell and vision as well as skeletal muscle manifestations. The neuroinvasive nature of SARS-CoV-2 may contribute to the acute respiratory failure of COVID-19. SARS-CoV-1 virus was detected in the brain of infected patients along with neuronal necrosis and glial hyperplasia. In SARS-CoV-2, modifications of crucial cellular pathways [mitochondrial function, proteolysis, lipid metabolism] known to be implicated in cellular aging and in neurodegenerative diseases occur. Adamantanes, [amantadine and the structurally-related memantine] are employed for the treatment of disorders of consciousness while also manifesting effective antiviral properties. Clinical studies and Case Reports at this early stage of COVID-19 reveal evidence of a protective effect of amantadine in infected patients with benefit being ascribed to amantadine’s effects on viral release into the host cell via mechanisms involving the E channel of the virus or by the agent’s down-regulation of the host protease Cathepsin L in addition to disruption of the lysosomal pathway. Memantine has potent neuroprotective actions in both wellestablished neurodegenerative diseases as well as in viral disorders in which it prevents neuronal cell loss and concomitantly reduces viral replication in a dose-dependent manner. Controlled clinical trials for the assessment of efficacy of these adamantanes for the prevention and treatment of COVID-19 are now indicated.

Gene Therapy for Pompe Disease: The Time is now.

Pompe disease (PD) is caused by the deficiency of the lysosomal enzyme acid α-glucosidase (GAA), resulting in systemic pathological glycogen accumulation. PD can present with cardiac, skeletal muscle, and central nervous system manifestations, as a continuum of phenotypes among two main forms: classical infantile-onset PD (IOPD) and late-onset PD (LOPD). IOPD is caused by severe GAA deficiency and presents at birth with cardiac hypertrophy, muscle hypotonia, and severe respiratory impairment, leading to premature death, if not treated. LOPD is characterized by levels of residual GAA activity up to ∼20% of normal and presents both in children and adults with a varied severity of muscle weakness and motor and respiratory deficit. Enzyme replacement therapy (ERT), based on repeated intravenous (i.v.) infusions of recombinant human GAA (rhGAA), represents the only available treatment for PD. Upon more than 10 years from its launch, it is becoming evident that ERT can extend the life span of IOPD and stabilize disease progression in LOPD; however, it does not represent a cure for PD. The limited uptake of the enzyme in key affected tissues and the high immunogenicity of rhGAA are some of the hurdles that limit ERT efficacy. GAA gene transfer with adeno-associated virus (AAV) vectors has been shown to reduce glycogen storage and improve the PD phenotype in preclinical studies following different approaches. Here, we present an overview of the different gene therapy approaches for PD, focusing on in vivo gene transfer with AAV vectors and discussing the potential opportunities and challenges in developing safe and effective gene therapies for the disease. Based on emerging safety and efficacy data from clinical trials for other protein deficiencies, in vivo gene therapy with AAV vectors appears to have the potential to provide a therapeutically relevant, stable source of GAA enzyme, which could be highly beneficial in PD.

Use of sodium 4-phenylbutyrate to define therapeutic parameters for reducing intracerebral hemorrhage and myopathy in Col4a1 mutant mice.

ABSTRACTCollagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) form heterotrimers that constitute a major component of nearly all basement membranes. COL4A1 and COL4A2 mutations cause a multisystem disorder that includes variable cerebrovascular and skeletal muscle manifestations. The pathogenicity of COL4A1 and COL4A2 mutations is generally attributed to impaired secretion into basement membranes. Sodium 4-phenylbutyrate (4PBA) is a US Food and Drug Administration-approved drug that promotes mutant heterotrimer secretion in vitro and in vivo. Here, we use different 4PBA treatment paradigms to define therapeutic parameters for preventing cerebrovascular and muscular pathologies in Col4a1 mutant mice. We show the efficacy of long-term 4PBA treatment in reducing the severity of intracerebral hemorrhages (ICHs) in Col4a1 mutant mice aged up to 8 months. In addition, we demonstrate that maximal efficacy of 4PBA on ICH and myopathy was achieved when treatment was initiated prenatally, whereby even transient 4PBA administration had lasting benefits after being discontinued. Importantly, postnatal treatment with 4PBA also reduced ICH and skeletal myopathy severities in Col4a1 mutant mice, which has significant clinical implications for patients with COL4A1 and COL4A2 mutations.This article has an associated First Person interview with the first author of the paper.

Toe walking in the mucopolysaccharides: Does it matter?

The skeletal muscle manifestations of late-onset Pompe disease (LOPD) cause significant gait impairment. However, the specific temporal and spatial characteristics of abnormal gait in LOPD have not been objectively analyzed or described in the literature. This pilot study evaluated the gait of 22 individuals with LOPD using the GAITRite® temporospatial gait analysis system. The gait parameters were compared to normal reference values, and correlations were made with standard measures of disease progression. The LOPD population demonstrated significant abnormalities in temporospatial parameters of gait including a trend towards decreased velocity and cadence, a prolonged stance phase, prolonged time in double limb support, shorter step and stride length, and a wider base of support. Precise descriptions and analyses of gait abnormalities have much potential in increasing our understanding of LOPD, especially in regards to how its natural history may be modified by the use of enzyme replacement therapy (ERT) and other interventions. Gait analysis may provide a sensitive early marker of the onset of clinical symptoms and signs, offer an additional objective measure of disease progression and the impact of intervention, and serve as a potentially important clinical endpoint. The additional data from comprehensive gait analysis may personalize and optimize physical therapy management, and the clarification of specific gait patterns in neuromuscular diseases could be of clinical benefit in the ranking of a differential diagnosis.

Characterization of gait in late onset Pompe disease.

The skeletal muscle manifestations of late-onset Pompe disease (LOPD) cause significant gait impairment. However, the specific temporal and spatial characteristics of abnormal gait in LOPD have not been objectively analyzed or described in the literature. This pilot study evaluated the gait of 22 individuals with LOPD using the GAITRite® temporospatial gait analysis system. The gait parameters were compared to normal reference values, and correlations were made with standard measures of disease progression. The LOPD population demonstrated significant abnormalities in temporospatial parameters of gait including a trend towards decreased velocity and cadence, a prolonged stance phase, prolonged time in double limb support, shorter step and stride length, and a wider base of support. Precise descriptions and analyses of gait abnormalities have much potential in increasing our understanding of LOPD, especially in regards to how its natural history may be modified by the use of enzyme replacement therapy (ERT) and other interventions. Gait analysis may provide a sensitive early marker of the onset of clinical symptoms and signs, offer an additional objective measure of disease progression and the impact of intervention, and serve as a potentially important clinical endpoint. The additional data from comprehensive gait analysis may personalize and optimize physical therapy management, and the clarification of specific gait patterns in neuromuscular diseases could be of clinical benefit in the ranking of a differential diagnosis.

G.O.25: Follistatin Gene Therapy for Becker Muscular Dystrophy

Becker muscular dystrophy (BMD), a dystrophinopathy with milder skeletal muscle manifestations compared to Duchenne muscular dystrophy, characteristically demonstrates weakness of knee extensors (KE), accompanied by muscle atrophy and fibrosis. The weakness predisposes to gait impairment and loss of ambulation. Myostatin, a member of the TGF-<i>β</i> superfamily of signal peptides, is expressed in skeletal muscle, acting through the activin type IIB (ACTRIIB) receptor. Follistatin, a myostatin antagonist, inhibits this pathway resulting in muscle hypertrophy, and improved muscle strength. FS315 and FS288 are two isoforms of follistatin generated by alternative splicing. FS315 has no cell-surface affinity providing a safety margin avoiding pituitary–gonadal axis complications. FS344 is the precursor cDNA to FS315. When FS344 is delivered to mdx mice in adeno-associated virus (AAV1. CMV. FS344), muscle mass and strength increase. Similar findings are seen in non-human primates without safety concerns. Six BMD patients, 18years and older with proven in-frame DMD gene mutations were enrolled in a clinical trial. The first 3 subjects received 12 intramuscular (IM) injections of AAV1. CMV. FS344 at a total dose of 6e11 vg/kg in the quadriceps muscles bilaterally. A second cohort received the same number of IM injections at higher total dose (1.2e12 vg/kg). Studies extending beyond one year in Cohort 1 and for six months in Cohort 2 showed no adverse events. The distance walked (meters) on the 6-min walk test (6MWT) was the primary functional outcome measure. At one year the distance walked by two subjects in Cohort 1 increased by 125m and 58m; subject 3 improved modestly by 9m. In Cohort 2, one patient reaching the 6-month time point increased by 108 meters. For the entire group of BMD patients only a single patient declined in distance. Preliminary analysis of muscle biopsies favor increased muscle regeneration contributing to improved function.

Evaluating the Role of Inflammation in Chronic Airways Disease: The ERICA Study

Extrapulmonary manifestations are recognized to be of increasing clinical importance in Chronic Obstructive Pulmonary disease. To investigate cardiovascular and skeletal muscle manifestations of COPD, we developed a unique UK consortium funded by the Technology Strategy Board and Medical Research Council comprising industry in partnership with 5 academic centres. ERICA (Evaluating the Role of Inflammation in Chronic Airways disease) is a prospective, longitudinal, observational study investigating the prevalence and significance of cardiovascular and skeletal muscle manifestations of COPD in 800 subjects. Six monthly follow up will assess the predictive value of plasma fibrinogen, cardiovascular abnormalities and skeletal muscle weakness for death or hospitalization.As ERICA is a multicentre study, to ensure data quality we sought to minimise systematic observer error due to variations in investigator skill, or adherence to operating procedures, by staff training followed by assessment of inter- and intra-observer reliability of the four key measurements used in the study: pulse wave velocity (PWV), carotid intima media thickness (CIMT), quadriceps maximal voluntary contraction force (QMVC) and 6-minute walk distance (6MWT). This report describes the objectives and methods of the ERICA trial, as well as the inter- and intra-observer reliability of these measurements.

A syndrome of congenital hyperinsulinism and rhabdomyolysis is caused by KCNJ11 mutation

BackgroundCongenital hyperinsulinism is a genetically heterogeneous disorder, but mutations in the components of the ATP-sensitive potassium channel K(ATP) account for more than a third of all isolated congenital hyperinsulinism cases....

P129 Skeletal muscle weakness, not arterial stiffness, differs according to GOLD group in COPD

IntroductionIn the GOLD 2011 COPD classification, patients in Group D are considered to be at highest risk of mortality, due to airflow limitation and exacerbations and also to be most...

Envolvimento das musculaturas esquelética e cardíaca na esclerose sistêmica

Patients with systemic sclerosis (SSc) can have muscle involvement in the form of myositis or non-infl ammatory myopathy. The muscle involvement can be associated with left ventricular dysfunction (LVD) in patients with SSc, resulting in worse prognosis. Eighty-seven patients of the Hospital de Clínicas of the Universidade Federal do Paraná, diagnosed with SSc, were assessed regarding the presence of skeletal muscle manifestations and their relation with LVD. A 42.5% prevalence of muscle involvement was observed in the patients studied, as well as a positive correlation with the diffuse form of the disease. Excluding other causes of LVD, three of the four patients with ejection fraction below the normal reference value had alteration of the muscle strength, atrophy and/or serum creatine phosphokinase (CPK) elevation.

TNFα receptor genotype influences smoking-induced muscle-fibre-type shift and atrophy in mice

Systemic manifestations of chronic obstructive pulmonary disease (COPD) include muscle wasting, and tumour necrosis factor alpha (TNFalpha) could represent a major inducer of these processes. We studied skeletal muscle histology in a murine model of cigarette smoke (CS)-induced COPD, comparing mice with different TNFalpha receptor genotypes. Muscles from hind limbs of wild type (WT), TNFalpha receptor 1 knockout (TNF alpha R1KO) and TNF alpha R2KO mice were prepared and weighed. The lower body weight, which was observed in CS-exposed WT and TNF alpha R1KO mice, was paralleled by reduced weights of gastrocnemius and biceps femoris muscle. The gastrocnemius muscle was evaluated for muscle fibre apoptosis and atrophy, and fibre-type distribution. CS-induced apoptosis was observed in all genotypes, while a significant reduction of cross-sectional areas of myofibres was present only in TNF alpha R2KO mice. A CS-induced fibre-type shift from the IIa to the IIb phenotype was observed in WT mice, an increase of muscle-fibre-type IIx was noticed in CS-exposed TNF alpha R2KO mice. Our data suggest that the skeletal muscle manifestations associated with this murine COPD model are under complex regulation by both TNFalpha receptors, but that TNF alpha R2 may be the most important determinant for the outcome of CS-induced myofibre apoptosis.

A longitudinal physical profile assessment of skeletal muscle manifestations in myotonic dystrophy.

To develop an assessment that describes the skeletal muscle manifestations in myotonic dystrophy subjects and then use it to quantify the presentation of skeletal muscle disability and to show change over time. A quantified skeletal muscle assessment was developed and applied three times over a two-year period at intervals around 12 months. Thirty-six subjects with myotonic dystrophy and 20 subjects without neuromuscular disability were evaluated. The assessment comprised manual muscle testing of five pairs of muscles, measuring neck flexor strength with a strain gauge, respiratory function tests, power and lateral pinch grip strength, all tests of impairment. Assessment of the ability to move from sitting to standing and fasten buttons tested disability. Results from subjects with myotonic dystrophy were compared to the normal data. The subjects with myotonic dystrophy were significantly weaker in proximal upper limb muscles, quadriceps, tibialis anterior muscles and neck flexor muscles as well as power and lateral pinch grips. There was also significant reduction in forced expiratory volume at one second (FEV1) and forced vital capacity (FVC). Significant disability was seen in the myotonics in moving from sitting to standing and in fastening buttons. Over the two-year study period proximal upper limb and lower limb muscle strength, FVC and sit-to-stand ability declined significantly. Power grip declined but lateral pinch grip and FEV1 improved significantly. Button fastening ability improved significantly. The test developed was shown to be reliable and sensitive to the change in skeletal muscle manifestations in subjects with myotonic dystrophy who were shown to be significantly weaker than normal subjects.