Muscle Deficits Research Articles

Persistent Musculoskeletal Deficits in Pediatric, Adolescent and Young Adult Survivors of Allogeneic Hematopoietic Stem-Cell Transplantation.

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a common therapy for pediatric hematologic malignancies. With improved supportive care, addressing treatment-related late effects is at the forefront of survivor long-term health and quality of life. We previously demonstrated that alloHSCT survivors had increased adiposity, decreased lean mass, and lower bone density and strength, 7 years (median) from alloHSCT compared to their healthy peers. Yet it is unknown whether these deficits persist. Our longitudinal study characterized changes in muscle and bone over a period of 3.4 (range, 2.0 to 4.9) years in 47 childhood alloHSCT survivors, age 5-26 years at baseline (34% female). Tibia cortical bone geometry and volumetric density and lower leg muscle cross-sectional area (MCSA) were assessed via peripheral quantitative computed tomography (pQCT). Anthropometric and pQCT measurements were converted to age, sex, and ancestry-specific standard deviation scores, adjusted for leg length. Muscle-specific force was assessed as strength relative to MCSA adjusted for leg length (strength Z-score). Measurements were compared to a healthy reference cohort (n=921), age 5-30 years (52% female). At baseline and follow-up, alloHSCT survivors demonstrated lower height Z-scores, weight Z-scores, and leg length Z-scores compared to the healthy reference cohort. Deficits in MCSA, trabecular volumetric bone density, and cortical bone size and estimated strength (section modulus) were evident in survivors (all p < 0.05). Between the two study time points, anthropometric, muscle, and bone Z-scores did not change significantly in alloHSCT survivors. Approximately 15% and 17% of alloHSCT survivors had MCSA and section modulus Z-score < -2.0, at baseline and follow-up, respectively. Furthermore, those with a history of total body irradiation compared to those without demonstrated lower MCSA at follow-up. The persistent muscle and bone deficits in pediatric alloHSCT survivors support the need for strategies to improve bone and muscle health in this at-risk population. © 2022 American Society for Bone and Mineral Research (ASBMR).

What Psychosocial and Physical Characteristics Differentiate Office Workers Who Develop Standing-Induced Low Back Pain? A Cross-Sectional Study.

This study examines demographic, physical and psychosocial factors associated with an increase in low back pain (LBP) during a one-hour standing task. A cross-sectional survey with 40 office workers was conducted. The primary outcome was pain severity during a one-hour standing task recorded every 15 min using a 100 mm Visual Analogue Scale (VAS). Participants were defined as pain developers (PD), if they reported a change in pain of ≥10 mm from baseline, or non-pain developers (NPD). Physical outcomes included participant-rated and examiner-rated trunk and hip motor control and endurance. Self-report history of LBP, physical activity, psychosocial job characteristics, general health and pain catastrophising were collected. Fourteen participants were PD. Hip abduction, abdominal and spinal muscle endurance was lower for PD (p ≤ 0.05). PD had greater self-reported difficulty performing active hip abduction and active straight leg raise tests (p ≤ 0.04). Those reporting a lifetime, 12 month or 7-day history of LBP (p < 0.05) and lower self-reported physical function (p = 0.01) were more likely to develop LBP during the standing task. In conclusion, a history of LBP, reduced trunk and hip muscle endurance and deficits in lumbopelvic/hip motor control may be important to consider in office workers experiencing standing-induced LBP.

OMICs AND AI APPROACHES FOR MUSCLE DISEASES: O.05 Whole exome sequencing identifies compound heterozygous missense variants in the LOXL4 gene: a novel candidate cause of contractural myopathy

Joint contractures are recurrent and sometimes prominent features in neuromuscular disorders, most notably in extracellular matrix (ECM)-related myopathies, such as COL6-related disorders (COL6-RD). Here, we report a patient with an atypical clinical presentation of congenital arthrogryposis, associated with distal hyperlaxity, proximal muscle deficit, dysphonia, dysphagia, mild ptosis and preserved respiratory function. At age 15, a COL6-RD was evoked and immunostaining of cutaneous fibroblasts from the patient revealed a subtle impairment of COLVI secretion; however, no mutation in the COL6A1-3 genes was identified.

LIMB GIRDLE MUSCULAR DYSTROPHIES: P.138 Systemic dose-finding study with AAV-Mediated gamma-sarcoglycan gene therapy for treatment of muscle deficits in LGMD2C Mice

Limb-girdle muscular dystrophy (LGMD) type 2C results from mutations in the γ-sarcoglycan gene, causing loss of functional protein. It is characterized by muscle weakness and progressive muscle wasting. The sarcoglycans (α, β, γ, and δ-SG) are structural proteins localized at the cell membrane of muscle fibers that together with dystrophin and other proteins make up the dystrophin-associated protein complex (DAPC). Loss of functional protein in this complex results in an unstable sarcolemma leading to eventual myofiber death.

Optimizing Outcomes With Physical Therapy Treatment for IndividuALs Surviving an Intensive Care Units Admission for COVID-19 (OPTImAL)—A Protocol for a Single Center Prospective Study

Purpose: Survivors of acute respiratory failure develop persistent muscle weakness and deficits in cardiopulmonary endurance leading to limited physical function. Early data from the COVID-19 pandemic suggest a high incidence of critically ill patients admitted to intensive care units (ICU) will require mechanical ventilation for acute respiratory failure. Patients with COVID-19 that survive an admission to the ICU are expected to suffer from physical and cognitive impairments that will limit quality of life and return to prehospital level of function. The primary aim of this study is to evaluate the safety and feasibility of providing combined ICU aftercare (ICU Recovery Clinic) and 8 weeks of physical therapy treatment for patients surviving an admission to ICU for COVID-19. The secondary aims will be to explore trends of effect on physical, mental, and cognitive recovery as well as the impact on return to work, readmission rates, and mortality. Methods: This is a protocol to describe a single-center, prospective phase I feasibility study in patients surviving ICU admission for COVID-19. We hypothesize that this novel combination is (1) feasible to provide for patients surviving COVID-19, will (2) improve physical function and exercise capacity measured by performance on 6-minute walk test and Short Performance Physical Battery, and (3) reduce incidence of anxiety, depression, and post-traumatic stress assessed with Hospital Anxiety and Depression Scale and the Impact of Events Scale-Revised. Safety will be assessed based on occurrence of adverse events and feasibility will be measured by adherence and attrition. Repeated measures analysis of variance will be used to assess change in outcomes from baseline to 3- and 6-months after institutional discharge. Results: We present the protocol of this study that has already received ethics approval at the University of Kentucky with enrollment commenced on May 1, 2020. Conclusions: The results of this study will support the feasibility of providing ICU follow-up treatment and physical therapy treatment for patients surviving critical illness for COVID-19 and will assess the effectiveness. We plan to disseminate study results in peer-reviewed journals as well as presentation at physical therapy and critical care national and international conferences.

Preoperative paraspinal neck muscle characteristics predict early onset adjacent segment degeneration in anterior cervical fusion patients: A machine-learning modeling analysis.

Early onset adjacent segment degeneration (ASD) can be found within six months after anterior cervical discectomy and fusion (ACDF). Deficits in deep paraspinal neck muscles may be related to early onset ASD. This study aimed to determine whether the morphometry of preoperative deep neck muscles (multifidus and semispinalis cervicis) predicted early onset ASD in patients with ACDF. Thirty-two cases of early onset ASD after a two-level ACDF and 30 matched non-ASD cases were identified from a large-scale cohort. The preoperative total cross-sectional area (CSA) of bilateral deep neck muscles and the lean muscle CSAs from C3 to C7 levels were measured manually on T2-weighted magnetic resonance imaging. Paraspinal muscle CSA asymmetry at each level was calculated. A support vector machine (SVM) algorithm was used to identify demographic, radiographic, and/or muscle parameters that predicted proximal/distal ASD development. No significant between-group differences in demographic or preoperative radiographic data were noted (mean age: 52.4 ± 10.9 years). ACDFs comprised C3 to C5 (n = 9), C4 to C6 (n = 20), and C5 to C7 (n = 32) cases. Eighteen, eight, and six patients had proximal, distal, or both ASD, respectively. The SVM model achieved high accuracy (96.7%) and an area under the curve (AUC = 0.97) for predicting early onset ASD. Asymmetry of fat at C5 (coefficient: 0.06), and standardized measures of C7 lean (coefficient: 0.05) and total CSA measures (coefficient: 0.05) were the strongest predictors of early onset ASD. This is the first study to show that preoperative deep neck muscle CSA, composition, and asymmetry at C5 to C7 independently predicted postoperative early onset ASD in patients with ACDF. Paraspinal muscle assessments are recommended to identify high-risk patients for personalized intervention.

A Role of Lamin A/C in Preventing Neuromuscular Junction Decline in Mice

During aging, skeletal muscles become atrophic and lose contractile force. Aging can also impact the neuromuscular junction (NMJ), a synapse that transmits signals from motoneurons to muscle fibers to control muscle contraction. However, in contrast to muscle aging that has been studied extensively, less is known about the molecular mechanisms of NMJ aging although its structure and function are impaired in aged animals. To this end, we performed RNA sequencing (RNA-seq) analysis to identify genes whose expression in synapse-rich region is altered. Gene ontology (GO) analysis highlighted genes relating to nuclear structure or function. In particular, lamin A/C, an intermediate filament protein critical for the interphase nuclear architecture, was reduced. Remarkably, mutation of lamin A/C in muscles or motoneurons had no effect on NMJ formation in either sex of mice, but the muscle mutation caused progressive denervation, acetylcholine receptor (AChR) cluster fragmentation, and neuromuscular dysfunction. Interestingly, rapsyn, a protein critical to AChR clustering, was reduced in mutant muscle cells; and expressing rapsyn in muscles attenuated NMJ deficits of HSA-Lmna-/- mice. These results reveal a role of lamin A/C in NMJ maintenance and suggest that nuclear dysfunction or deficiency may contribute to NMJ deficits in aged muscles.SIGNIFICANCE STATEMENT This study provides evidence that lamin A/C, a scaffolding component of the nuclear envelope, is critical to maintaining the NMJ in mice. Its muscle-specific mutation led to progressive NMJ degeneration in vivo We showed that the mutation reduced the level of rapsyn, a protein necessary for acetylcholine receptor (AChR) clustering; and expression of rapsyn in muscles attenuated NMJ deficits of HSA-Lmna-/- mice. These results reveal a role of lamin A/C in NMJ maintenance and suggest that nuclear dysfunction or deficiency may contribute to NMJ deficits in aged muscles.

Radiologic Assessment of Muscle and Fat Stores in Long-Term Type I Diabetics Referred for Pancreas Transplant Compared to Healthy Controls.

Type 1 diabetes (DM1) is associated with loss of skeletal muscle and bone mass and may affect body fat stores. This study employs computed tomography (CT) scans to assess the body composition of DM1 patients referred for pancreas transplant compared to healthy controls. A 1:1 case–control design matched study patients with otherwise healthy patients from the trauma database. Matching criteria included age ± 5 years, gender, and body mass index (BMI) ± 2kg/m2. Nutrition variables included serum albumin and protein levels, BMI, and CT measures of muscle mass and fat stores. There were 22 subjects and 22 controls (median DM1 duration 24 years). DM1 patients had less muscle mass and less subcutaneous fat but no difference in visceral fat. Patients with the greatest muscle deficit were those with DM1 greater than 20 years and those younger than age 40. DM1 patients maintain similar BMI and protein levels compared to healthy controls but have marked deficits of muscle and subcutaneous fat. These results inform the nutritional management of DM1 patients and quantify the muscle and fat deficits present in these patients. At highest risk are young patients and those with duration of DM1 over 20 years.

Muscle deficits with normal bone microarchitecture and geometry in young adults with well-controlled childhood-onset Crohn’s disease

Muscle-bone deficits are common in pediatric Crohn's disease; however, few studies have assessed long-term musculoskeletal outcomes in adults with childhood-onset Crohn's disease. This study assessed the prevalence of musculoskeletal deficits in young adults with childhood-onset Crohn's disease compared with healthy controls. High-resolution MRI and MR spectroscopy were used to assess bone microarchitecture, cortical geometry and muscle area, and adiposity at distal femur and bone marrow adiposity (BMA) at lumbar spine. Muscle function and biomarkers of the muscle-bone unit were also assessed. Twenty-seven adults with Crohn's disease with median (range) age 23.2 years (18.0, 36.1) and 27 age and sex-matched controls were recruited. Trabecular microarchitecture, cortical geometry and BMA were not different between Crohn's disease and controls (P > 0.05 for all). Muscle area was lower (P = 0.01) and muscle fat fraction was higher (P = 0.04) at the distal femur in Crohn's disease compared to controls. Crohn's disease participants had lower grip strength [-4.3 kg (95% confidence interval (CI), -6.8 to -1.8), P = 0.001] and relative muscle power [-5.0 W/kg (95% CI, -8.8 to -1.2), P = 0.01]. Crohn's disease activity scores negatively associated with trabecular bone volume (r = -0.40, P = 0.04) and muscle area (r = -0.41, P = 0.03). Young adults with well-controlled Crohn's disease managed with contemporary therapies did not display abnormal bone microarchitecture or geometry at the distal femur but exhibited muscle deficits. The observed muscle deficits may predispose to musculoskeletal morbidity in future and interventions to improve muscle mass and function warrant investigation.

Hemifacial Microsomia Review: Recent Advancements in Understanding the Disease.

Hemifacial microsomia (HFM) is the second most common congenital disability of the face, with a prevalence of 1 in 3000 to 5600 live births. Although etiology is still not fully understood, including both genetics and environmental factors, the latest reports indicate the prominence of premature loss of the neural crest cells. What is more, a deficit of muscles of mastication, except the masseter, correlates in the pathomechanism of mandibular underdevelopment. Due to the significant phenotypic diversification, the typical picture of HFM cannot be determined. It may present as an esthetic concern-minor asymmetry with deformed auricle, and on the contrary, as microtia/anotia with conductive type hearing loss, hypoplastic mandible, and microphthalmia, impairing patient's daily activities. Referring to psychosocial problems, it has been proved that in population with HFM, there is a modestly elevated risk for behavior problems, social competence, and less acceptance. Over the years, more comprehensive methods of assessing the extent and severity of the HFM as the OMENS (+) classification have emerged. The authors like to summarize and present for plastic surgery resident and plastic surgeons the critical features of HFM, including the epidemiology, clinical presentation, pathogenesis, and innovative management reported in the current literature.

Motor axonopathies in a mouse model of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease caused by deleterious mutations in the DMD gene which encodes the dystrophin protein. Skeletal muscle weakness and eventual muscle degradation due to loss of dystrophin are well-documented pathological hallmarks of DMD. In contrast, the neuropathology of this disease remains understudied despite the emerging evidence of neurological abnormalities induced by dystrophin loss. Using quantitative morphological analysis of nerve sections, we characterize axonopathies in the phrenic and hypoglossal (XII) nerves of mdx mice. We observe dysfunction in these nerves – which innervate the diaphragm and genioglossus respectively – that we propose contributes to respiratory failure, the most common cause of death in DMD. These observations highlight the importance in the further characterization of the neuropathology of DMD. Additionally, these observations underscore the necessity in correcting both the nervous system pathology in addition to skeletal muscle deficits to ameliorate this disease.

Effects of Cesarean Section and Vaginal Delivery on Abdominal Muscles and Fasciae.

Background and objectives: Possible disorders after delivery may interfere with the quality of life. The aim of this study was to ascertain whether abdominal muscles and fasciae differ in women depending on whether they experienced transverse cesarean section (CS) or vaginal delivery (VA) in comparison with healthy nulliparous (NU). Materials and methods: The thicknesses of abdominal muscles and fasciae were evaluated by ultrasound in 13 CS, 10 VA, and 13 NU women (we examined rectus abdominis (RA); external oblique (EO); internal oblique (IO); transversus abdominis (TrA); total abdominal muscles (TAM = EO + IO + TrA); inter-rectus distance (IRD); thickness of linea alba (TLA); rectus sheath (RS), which includes anterior fascia of RS and posterior fascia of RS (P-RS); loose connective tissue between sublayers of P-RS (LCT); abdominal perimuscular fasciae (APF), which includes anterior fascia of EO, fasciae between EO, IO, and TrA, and posterior fascia of TrA). Data on pain intensity, duration, and location were collected. Results: Compared with NU women, CS women had wider IRD (p = 0.004), thinner left RA (p = 0.020), thicker right RS (p = 0.035) and APF (left: p = 0.001; right: p = 0.001), and IO dissymmetry (p = 0.009). VA women had thinner RA (left: p = 0.008, right: p = 0.043) and left TAM (p = 0.024), mainly due to left IO (p = 0.027) and RA dissymmetry (p = 0.035). However, CS women had thicker LCT (left: p = 0.036, right: p < 0.001), APF (left: p = 0.014; right: p = 0.007), and right IO (p = 0.028) than VA women. There were significant correlations between pain duration and the affected fasciae/muscles in CS women. Conclusions: CS women showed significant alterations in both abdominal fasciae and muscle thicknesses, whereas VA women showed alterations mainly in muscles. Thinner RA and/or dissymmetric IO, wider IRD, and thicker LCT and APF after CS may cause muscle deficits and alteration of fascial gliding, which may induce scar, abdominal, low back, and/or pelvic pain.

Potential therapeutic effects of plx cells in microgravity conditions

Background & Aim BACKGROUND - PLX are placenta-derived, mesenchymal-like adherent stromal cells that can be administered without the need for genetic matching. The PLX is currently in the late stage of Phase III multinational clinical trials for the treatment of critical limb ischemia and muscle injuries following surgery to repair hip fractures. The proposed mode of action is the release of soluble factors, such as cytokines and growth factors, to facilitate healing of damaged tissue by stimulating the body's natural repair processes. OBJECTIVE - To evaluate the potency of Placental eXpanded (PLX) cells, an allogenic, off-the-shelf, cell therapy product, in preventing adverse health outcomes during an extended period of simulated microgravity (hindlimb unloading, HU). Specifically, we assessed whether PLX treatment protects mice from adverse effects of simulated microgravity including immune system dysfunction, and deficits in muscle, bone, brain and marrow-derived osteoprogenitors. Methods, Results & Conclusion EXPERIMENT DESIGN -Animals: C57BL/6NJ mice; Four-month-old females at onset of treatment Treatment: Hindlimb unloading (HU) for 30 days and normally loaded controls (NL) in standard cages Intervention: PLX-PAD (maternal origin), PLX-R18 (fetal origin) or Sham (Plasmalyte) RESULTS - PLX treatment was well tolerated in a model for simulated weightlessness (HU) with no adverse effects on body weight and measures of neuroendocrine stress, such as circulating corticosterone levels and adrenal weight. In the hippocampus, a brain region important for cognition and memory, PLX prevented HU-induced decreases in protein levels of select cytokines. In contrast, PLX did not prevent HU-induced changes in circulating cytokine levels, bone loss, muscle atrophy nor immune cell differentials. CONCLUSIONS PLX treatment protected against some of the HU-induced changes in cytokine protein levels in the brain, confirming its immunomodulatory effects. Under the conditions of this study, PLX treatment did not prevent musculoskeletal deficits and immune cell population shifts caused by HU. PLX treatment was well tolerated in a model that simulates microgravity (HU) and therefore may be suitable for treating ischemic tissue damage due to injuries during long duration space travel; further studies are needed.

Skeletal muscle disease in rheumatoid arthritis: the center of cardiometabolic comorbidities?

Despite its critical roles in body movement, structure, and metabolism, skeletal muscle remains underappreciated in the context of rheumatoid arthritis. In rheumatoid arthritis, chronic inflammation, physical inactivity, and medication toxicities impair skeletal muscle. These skeletal muscle alterations contribute to continued rheumatoid arthritis disparities in physical function and cardiometabolic health. In the prebiologic disease-modifying antirheumatic drug era, rheumatoid arthritis skeletal muscle atrophy was the central feature of 'rheumatoid cachexia,' a hypermetabolic state driven by chronic systemic inflammation and muscle protein degradation. In the current era, rheumatoid arthritis muscle deficits are less visible, yet persist as a key component of 'sarcopenic obesity.' In rheumatoid arthritis sarcopenic obesity, chronic inflammation, physical inactivity, and medication toxicities contribute to muscle contractile deficits, inflammation, altered metabolism, and intramuscular adiposity, a key predictor of rheumatoid arthritis disability and insulin resistance. Rheumatoid arthritis skeletal muscle disease in the current era is defined by impaired contractile function (poor strength and endurance) and sarcopenic obesity (decreased muscle mass, increased fat mass, and intramuscular adiposity). These muscle impairments contribute to disability and cardiometabolic disease in rheumatoid arthritis. Management should focus on monitoring of rheumatoid arthritis muscle function and body composition, limiting potentially myotoxic drugs, and prescription of exercise training.

Body Composition in Young Adults Living With a Fontan Circulation: The Myopenic Profile.

BackgroundWe sought to characterize body composition abnormalities in young patients living with a Fontan circulation and explore potential pathophysiologic associations.Methods and ResultsTwenty‐eight patients with a Fontan circulation were prospectively recruited in this cross‐sectional study. Participants underwent cardiopulmonary exercise testing, dual‐energy X‐ray absorptiometry, echocardiography, and biochemical assessment. Mean age was 26±7 years. Skeletal muscle mass, estimated by appendicular lean mass index Z score, was reduced compared with reference data (−1.49±1.10, P<0.001). Percentage body fat Z score overall was within normal range (0.23±1.26, P=0.35), although 46% had elevated adiposity. Those with reduced skeletal muscle mass (appendicular lean mass index Z score of −1 or lower) had lower percent predicted oxygen pulse (55±15 versus 76±16%, P=0.002). Overall agreement between body mass index and dual‐energy X‐ray absorptiometry to assess adiposity was fair only (weighted [linear] κ coefficient: 0.53; 95% CI, 0.34–0.73) and slight in the setting of muscle mass deficiency (weighted κ coefficient: 0.32; 95% CI, 0.13–0.50). Appendicular lean mass was independently associated with absolute peak VO 2 (β=70.6 mL/min, P=0.001). Appendicular lean mass index Z score was inversely associated with hemoglobin (r=−0.4, P=0.04), and the degree of muscle deficit was associated with ventricular systolic impairment.ConclusionsYoung patients with a Fontan circulation have a body composition characterized by reduced skeletal muscle mass, which is associated with peak exercise capacity. Increased adiposity is common despite a normal body mass index. Low skeletal muscle mass is associated with systolic dysfunction and compensatory erythrocytosis.

Matrix Metalloproteinase 13 from Satellite Cells is Required for Efficient Muscle Growth and Regeneration.

Cell migration and extracellular matrix remodeling underlie normal mammalian development and growth as well as pathologic tumor invasion. Skeletal muscle is no exception, where satellite cell migration replenishes nuclear content in damaged tissue and extracellular matrix reforms during regeneration. A key set of enzymes that regulate these processes are matrix metalloproteinases (MMP)s. The collagenase MMP-13 is transiently upregulated during muscle regeneration, but its contribution to damage resolution is unknown. The purpose of this work was to examine the importance of MMP-13 in muscle regeneration and growth in vivo and to delineate a satellite cell specific role for this collagenase. Mice with total and satellite cell specific Mmp13 deletion were utilized to determine the importance of MMP-13 for postnatal growth, regeneration after acute injury, and in chronic injury from a genetic cross with dystrophic (mdx) mice. We also evaluated insulin-like growth factor 1 (IGF-1) mediated hypertrophy in the presence and absence of MMP-13. We employed live-cell imaging and 3D migration measurements on primary myoblasts obtained from these animals. Outcome measures included muscle morphology and function. Under basal conditions, Mmp13-/- mice did not exhibit histological or functional deficits in muscle. However, following acute injury, regeneration was impaired at 11 and 14 days post injury. Muscle hypertrophy caused by increased IGF-1 was blunted with minimal satellite cell incorporation in the absence of MMP-13. Mmp13-/- primary myoblasts displayed reduced migratory capacity in 2D and 3D, while maintaining normal proliferation and differentiation. Satellite cell specific deletion of MMP-13 recapitulated the effects of global MMP-13 ablation on muscle regeneration, growth and myoblast movement. These results show that satellite cells provide an essential autocrine source of MMP-13, which not only regulates their migration, but also supports postnatal growth and resolution of acute damage.

The Contribution of Environment to Impair Re‐Innervation in Age‐Related Failure of Muscle Regeneration Following Injury

An age‐related decline in the structure and function of the neuromuscular junction (NMJ) has been hypothesised to play an important role in the loss of muscle mass and force generating capacity that occurs during ageing and to contribute to the incomplete regeneration of skeletal muscle following damage.The aim of this study was to determine the relative levels of innervation of muscle fibres from adult and old wild type (WT) mice and in mice lacking superoxide dismutase (SOD1) SodKO mice prior to and during regeneration following extensive muscle damage induced by barium chloride (BaCl2). Based on the known role of environment as a contributor to the success of muscle regeneration, an additional aim was to test whether the deficits in innervation, muscle mass, and force generation seen in muscles of old mice was evident in muscles transplanted from old donors into adult hosts and vice versa.Male B6.Cg‐Tg (Thy1‐YFP) mice aged 8–10 months (adult) or 24 months (old), male adult (8–10 months) mice lacking SOD1 (C57Bl/6 Sod1KO mice) and male adult SOD1KO mice crossed with Thy1‐CFP (SOD1KO‐CFP) were used for the BaCl2 study. Mice were anaesthestised and the extensor digitorum longus (EDL) muscle was injected with 50ul BaCl2, (1.2% wt/vol in sterile saline). Adult and old WT mice were allowed to recover for up to 60 days. SOD1KO mice were studied prior to‐ and at 28 days post damage, the time point where failure in recovery of contractile force was seen in old WT mice.Male WT adult (6–8 months) and old (22 – 24 months) mice were used for the muscle transplant studies. EDL muscles were transferred to the new host, where the tendons were hen repaired and the nerve from the host implanted into the transplanted muscle. At 28 and 60 days following transplantation, mice were culled and EDL muscles were removed, contractile function measured and NMJ structure examined.For analysis of NMJ structure the post‐synaptic regions of fixed EDL muscles were stained with alpha‐bungarotoxin and Dapi. Multiple images were collected from each muscle and the innervation status of each NMJ was assessed.Data demonstrated that although the 30% full denervation of NMJ structure in association with some reduction in fibre diameter may be responsible for the 35% muscle force deficit that occurred in mice that lack SOD1, the level of denervation could not solely explain the substantial force deficit in muscle from old WT mice following extensive damage and regeneration. In contrast, data support the conclusion that the deficit in force seen in muscles from old WT mice following regeneration from damage is caused by the environment in which the muscle regenerated since transplantation of EDL muscles from either adult or old mice into old mice leads to defective regeneration of those muscles; however, experiments aimed at determining whether the environment impacted the effectiveness of re‐innervation remained inconclusive with substantial disruption evident in all instances.Support or Funding InformationWith thanks to National Institute of Ageing (AG051442) and University of Liverpool for their support.

Lipid composition and organization helps plasma membrane repair and offers novel therapeutic target to treat degenerative muscle disease

The plasma membrane of all cells is routinely injured, with considerable investigative effort focused on understanding how proteins help repair this injury. Despite being the most abundant component of the plasma membrane, the role of lipids in repairing injured mammalian cells has remained unexplored. Through systematic live cell imaging we have examined the involvement of lipids in plasma membrane repair following injury. This shows that change in composition and localization of plasma membrane lipids is crucial for repair. Specifically, we find that cell injury results in a rapid change in local cholesterol and sphingomyelin content, and failure of which increases membrane fluidity and compromises membrane repair. Plasma membrane injury also alters the local composition of phospholipids including PIP2 and diacylglycerol (DAG), which is required for the repair of the injured plasma membrane. Failure of these lipid changes in muscle fibers injured by mechanical or other activity, results in myofiber death and Limb Girdle Muscular Dystrophy (LGMD2B). To target this deficit we developed a gene therapy approach to exogenously modify the plasma membrane lipid composition in a mouse model of LGMD2B. This approach improved the repair of the dystrophic muscle, attenuated myofiber death and improved muscle strength and histopathology. These findings provide direct evidence of the diverse roles of lipids in not only maintaining the integrity of the plasma membrane, but also in re‐establishing its integrity following injury. Here, we establish the clinical relevance of the structural and signaling roles of lipids in cell repair, and identify therapeutic approaches that address these deficits in muscle diseases.Support or Funding InformationThis work is supported by R01AR055686 from NIH/NIAMS.

ТРУДНОСТИ РАННЕЙ ДИАГНОСТИКИ И ОПЕРАТИВНОЙ КОРРЕКЦИИ ТЯЖЕЛОГО ВРОЖДЕННОГО ПОРОКА СЕРДЦА – ОБЩЕГО ОТКРЫТОГО АТРИОВЕНТИКУЛЯРНОГО КАНАЛА У РЕБЕНКА ПЕРВОГО ГОДА ЖИЗНИ

Общий открытый атриовентрикулярный канал (ООАВК) или атриовентрикулярный септальный дефект (АВСД) включает большую группу аномалий, объединенных одним анатомическим признаком: дефицитом мышечной и мембранозной атриовентикулярной перегородки (АV-перегородки) от межпредсердного сообщения до функционально единственного желудочка. Этот порок составляет 4 % от всех ВПС. У 75 % больных с ООАВК констатируют синдром Дауна. В данной статье рассмотрен клинический случай ребенка с ООАВК, сочетающегося с синдромом Дауна. После тщательного обследования, уточнения диагноза ребенку проведена оперативная коррекция данного порока по модифицированной «австралийской» технике. Авторы обращают внимание на трудности ранней диагностики тяжелого врожденного порока сердца.

Complicated Muscle-Bone Interactions in Children with Cerebral Palsy.

The goal of this review is to highlight the deficits in muscle and bone in children with cerebral palsy (CP), discuss the muscle-bone relationship in the CP population, and identify muscle-based intervention strategies that may stimulate an improvement in their bone development. The latest research suggests that muscle and bone are both severely underdeveloped and weak in children with CP, even in ambulatory children with mild forms of the disorder. The small and low-performing muscles and limited participation in physical activity are likely the major contributors to the poor bone development in children with CP. However, the muscle-bone relationship may be complicated by other factors, such as a high degree of fat and collagen infiltration of muscle,atypical muscle activation, andmuscle spasticity. Muscle-based interventions, such as resistance training, vibration, and nutritional supplementation, have the potential to improve bone development in children with CP, especially if they are initiated before puberty. Studies are needed to identify the muscle-related factors with the greatest influence on bone development in children with CP. Identifying treatment strategies that capitalize on the relationship between muscle and bone, while also improving balance, coordination, and physical activity participation, is an important step toward increasing bone strength and minimizing fractures in children with CP.