Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) therapy decreases lean body mass and appendicular skeletal muscle mass index even until one year after the final treatment in patients with B-cell non-Hodgkin lymphoma.

Sarcopenia is an independent prognostic factor for several solid cancers, including B-cell non-Hodgkin lymphoma (B-NHL). However, previous reports have measured the parameters of loss of skeletal muscle as sarcopenia only once before chemotherapy and have predicted poor outcomes. In this study, changes in body composition were measured in patients who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) therapy for B-NHL using the InBody 720 analyzer throughout the therapy. Twenty-seven patients who achieved complete remission and survived for one year after the last cycle were included in the study. Body composition was evaluated immediately before initiation and fourth cycle, and one month and one year after the last cycle. Throughout the follow-up period, the lean body mass index (LBMI) and appendicular skeletal muscle mass index (ASMI) showed significant transient decreases even one year following the last cycle (p < 0.001, p = 0.002, respectively). Body fat index (BFI) and body fat percentage (BF%) decreased until one month after the last cycle; however, they reached levels higher than the baseline levels, +22.1% and +15.9%, respectively, at 1 year from the last cycle. The loss of skeletal muscle mass did not recover even one year after the last cycle. Interventions in nutritional management are needed to prevent sarcopenia in patients treated with R-CHOP therapy.

Adjunct role of potassium-rich vegetarian diet and a novel potassium food supplement to improve pain in chronic rheumatoid arthritis on supervised standard care: a randomised controlled study.

Introduction: An earlier food survey showed dietary potassium deficiency in rheumatoid arthritis (RA). Objective: To evaluate an adjunct role of oral potassium to reduce joint pain in RA. Methods: 172 consenting eligible symptomatic patients (median duration 6.5 years) on standard care were randomised into an assessor blind, parallel efficacy, controlled, prospective, multiarm single-centre study (80% power, drug trial design) of 16 weeks duration-arm A (potassium-rich vegetarian diet), arm B (arm A plus novel potassium food supplement) and arm C (control, regular diet). Standard efficacy (American College of Rheumatology recommendation) and safety and diet intake (3-day recall) were assessed at monthly intervals (protocol). Standard soft-ware package (SPSS V.20) was used for statistical analysis; analysis of variance), Mann-Whitney statistic and χ2 test.; significant p<0.05, two sided). Study arms were found matched at baseline. Background RA medication remained stable. Preset target for increased potassium intake (India standards) were mostly achieved and participants remained normokalemic. Results: 155 patients (90.1%) completed the study and several showed improvement (maximum improved measures in arm B). Potassium intervention was safe and well tolerated. Adverse events were mild; none caused patient withdrawal. On comparison, the mean change in pain visual analogue scale (-2.23, 95% CI -2.99 to -1.48) at week 16 (primary efficacy) from baseline was significantly superior in arm B (per protocol analysis). A high daily potassium intake (5-7.5 g, arm B) was significantly associated with low pain (study completion); OR 2.5 (univariate analysis), likelihood ratio 2.9 (logistic regression). Compliance (intervention), diet record and analysis, RA medication and absence of placebo were potential confounders. Conclusion: High oral potassium intake, based on a suitable vegetarian diet and food supplement, reduced joint pain and improved RA. It was a safe adjunct to standard care, Further validation studies are required. Trial registration: CTRI/2022/03/040726; Clinical Trial Registry of India.

A standardized herbal combination of Astragalus membranaceus and Paeonia japonica promotes skeletal muscle hypertrophy in a treadmill exercise mouse model.

Background: Maintaining a normal range of muscle mass and function is crucial not only for sustaining a healthy life but also for preventing various disorders. Numerous nutritional or natural resources are being explored for their potential muscle hypertrophic properties. Aim: We aimed to evaluate the muscle hypertrophic effects of APX, a 1:1 mixture of Astragalus membranaceus and Paeonia japonica. In addition to the myotube differentiation cell assay, we utilized a weighted exercise-based animal model and evaluated changes in muscle hypertrophy using dual-energy X-ray absorptiometry (DXA) and histological analysis. Results: The 8-week treadmill exercise led to notable decreases in body weight and fat mass but an increase in muscle mass compared to the control group. Administration of APX significantly accelerated muscle mass gain (p < 0.05) without altering body weight or fat mass compared to the exercise-only group. This muscle hypertrophic effect of APX was consistent with the histologic size of muscle fibers in the gastrocnemius (p > 0.05) and rectus femoris (p < 0.05), as well as the regulation of myogenic transcription factors (MyoD and myogenin), respectively. Furthermore, APX demonstrated a similar action to insulin-like growth factor 1, influencing the proliferation of C2C12 myoblast cells (p < 0.01) and their differentiation into myotubes (p < 0.05) compared to the control group. Conclusion: The present study provides experimental evidence that APX has muscle hypertrophic effects, and its underlying mechanisms would involve the modulation of MyoD and myogenin.

Aberrant evoked calcium signaling and nAChR cluster morphology in a SOD1 D90A hiPSC-derived neuromuscular model.

Familial amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder that is due to mutations in one of several target genes, including SOD1. So far, clinical records, rodent studies, and in vitro models have yielded arguments for either a primary motor neuron disease, or a pleiotropic pathogenesis of ALS. While mouse models lack the human origin, in vitro models using human induced pluripotent stem cells (hiPSC) have been recently developed for addressing ALS pathogenesis. In spite of improvements regarding the generation of muscle cells from hiPSC, the degree of maturation of muscle cells resulting from these protocols has remained limited. To fill these shortcomings, we here present a new protocol for an enhanced myotube differentiation from hiPSC with the option of further maturation upon coculture with hiPSC-derived motor neurons. The described model is the first to yield a combination of key myogenic maturation features that are consistent sarcomeric organization in association with complex nAChR clusters in myotubes derived from control hiPSC. In this model, myotubes derived from hiPSC carrying the SOD1 D90A mutation had reduced expression of myogenic markers, lack of sarcomeres, morphologically different nAChR clusters, and an altered nAChR-dependent Ca2+ response compared to control myotubes. Notably, trophic support provided by control hiPSC-derived motor neurons reduced nAChR cluster differences between control and SOD1 D90A myotubes. In summary, a novel hiPSC-derived neuromuscular model yields evidence for both muscle-intrinsic and nerve-dependent aspects of neuromuscular dysfunction in SOD1-based ALS.

Cross-sectional and longitudinal analysis of bone age maturation during peri-pubertal growth in children with type I, III and IV osteogenesis imperfecta.

Osteogenesis imperfecta (OI)is a rare genetically heterogeneous disorder caused by changes in the expression or processing of type I collagen. Clinical manifestations include bone fragility, decreased linear growth, and skeletal deformities that vary in severity. In typically growing children, skeletal maturation proceeds in a predictable pattern of changes in the size, shape, and mineralization on the hand and wrist bones that can be followed radiographically known at the bone age. Assessment of bone age can be clinically used to assess time remaining for linear growth, and the onset and duration of puberty, both of which can be useful in determining the timing of some surgeries or the interpretation of other imaging modalities such as bone densitometry. Additionally, deviations in the expected maturation process of the bone age may prompt or assist in the work up of a significant delay or advancement in a child's growth pattern. The primary aim of our study was to determine whether the bone age in children with a skeletal disorder such as OI follow the same pattern and rate of bone maturation compared to a control population. Using participants from the Natural History Study of the Brittle Bone Disorders Consortium, we analyzed 159 left hand and wrist radiographs (bone age) for a cross-sectional analysis and 55 bone ages repeated at approximately 24 months for a longitudinal analysis of skeletal maturation. Bone ages were read by a pediatric endocrinologist and by an automated analysis using a program called BoneXpert. Our results demonstrated that in children with mild-to-moderate OI (types I and IV), the skeletal maturation is comparable to chronological age-mated controls. For those with more severe forms of OI (type III), there is a delayed pattern of skeletal maturation of less than a year (10.5 months CI 5.1-16) P = 0.0012) at baseline and a delayed rate of maturation over the two-year follow up compared to type I (P = 0.06) and type III (P = 0.02). However, despite these parameters being statistically different, they may not be clinically significant. We conclude the bone age, with careful interpretation, can be used in the OI population in a way that is similar to the general pediatric population.

Establishment and Validation of a Predictive Model for Sarcopenia Based on 2-D Ultrasound and Shear Wave Elastography in the Medial Gastrocnemius Muscle.

OBJECTIVE: To develop and validate a predictive model for sarcopenia. METHODS: A total of 240 subjects who visited our hospital between August 2021 and May 2023 were randomly divided by time of entry into a training set containing 2/3 of patients and a validation set containing 1/3 of patients. The muscle thickness (MT), echo intensity (EI), and shear wave velocity (SWV) of the medial gastrocnemius muscle were measured. Indicators that were meaningful in the univariate analysis in the training set were included in a binary logistic regression to derive a regression model, and the model was evaluated using a consistency index, calibration plot, and clinical validity curve. Diagnostic efficacy and clinical applicability were compared between the model and unifactorial indicators. RESULTS: Four meaningful variables, age, body mass index (BMI), MT, and SWV, were screened into the predictive model. The model was Logit Y = 21.292 + 0.065 × Age - 0.411 × BMI - 0.524 × MT - 3.072 × SWV. The model was well differentiated with an internally validated C-index of 0.924 and an external validation C-index of 0.914. The calibration plot predicted probabilities against actual probabilities showed excellent agreement. The specificity, sensitivity, and Youden's index of the model were 73.80%, 97.40%, and 71.20%, respectively, when using the diagnostic cut-off value of >0.279 for sarcopenia. The logistic model had higher diagnostic efficacy (p < 0.001) and higher net clinical benefit (p < 0.001) over the same threshold range compared to indicators. CONCLUSION: The logistic model of sarcopenia has been justified to have good discriminatory, calibrated, and clinical validity, and has higher diagnostic value than indicators.

Branched-chain amino acids and L-alanine supplementation ameliorate calcium dyshomeostasis in sarcopenia: New insights for nutritional interventions.

Introduction: During aging, sarcopenia and decline in physiological processes lead to partial loss of muscle strength, atrophy, and increased fatigability. Muscle changes may be related to a reduced intake of essential amino acids playing a role in proteostasis. We have recently shown that branched-chain amino acid (BCAA) supplements improve atrophy and weakness in models of muscle disuse and aging. Considering the key roles that the alteration of Ca2+-related homeostasis and store-operated calcium entry (SOCE) play in several muscle dysfunctions, this study has been aimed at gaining insight into the potential ability of BCAA-based dietary formulations in aged mice on various players of Ca2+ dyshomeostasis. Methods: Seventeen-month-old male C57BL/6J mice received a 12-week supplementation with BCAAs alone or boosted with two equivalents of L-alanine (2-Ala) or with dipeptide L-alanyl-L-alanine (Di-Ala) in drinking water. Outcomes were evaluated on ex vivo skeletal muscles indices vs. adult 3-month-old male C57BL/6J mice. Results: Ca2+ imaging confirmed a decrease in SOCE and an increase of resting Ca2+ concentration in aged vs. adult mice without alteration in the canonical components of SOCE. Aged muscles vs. adult muscles were characterized by a decrease in the expression of ryanodine receptor 1 (RyR1), the Sarco-Endoplasmic Reticulum Calcium ATPase (SERCA) pump, and sarcalumenin together with an alteration of the expression of mitsugumin 29 and mitsugumin 53, two recently recognized players in the SOCE mechanism. BCAAs, particularly the formulation BCAAs+2-Ala, were able to ameliorate all these alterations. Discussion: These results provide evidence that Ca2+ homeostasis dysfunction plays a role in the functional deficit observed in aged muscle and supports the interest of dietary BCAA supplementation in counteracting sarcopenia-related SOCE dysregulation.

Insights into the epitranscriptomic role of N6-methyladenosine on aging skeletal muscle.

The modification of RNA through the N6-methyladenosine (m6A) has emerged as a growing area of research due to its regulatory role in gene expression and various biological processes regulating the expression of genes. m6A RNA methylation is a post-transcriptional modification that is dynamic and reversible and found in mRNA, tRNA, rRNA, and other non-coding RNA of most eukaryotic cells. It is executed by special proteins known as "writers," which initiate methylation; "erasers," which remove methylation; and "readers," which recognize it and regulate the expression of the gene. Modification by m6A regulates gene expression by affecting the splicing, translation, stability, and localization of mRNA. Aging causes molecular and cellular damage, which forms the basis of most age-related diseases. The decline in skeletal muscle mass and functionality because of aging leads to metabolic disorders and morbidities. The inability of aged muscles to regenerate and repair after injury poses a great challenge to the geriatric populace. This review seeks to explore the m6A epigenetic regulation in the myogenesis and regeneration processes in skeletal muscle as well as the progress made on the m6A epigenetic regulation of aging skeletal muscles.

Accuracy and repeatability of 3D Photogrammetry to digitally reconstruct bones.

Advances in computer hardware and software permit the reconstruction of physical objects digitally from digital camera images. Given the varying shapes and sizes of human bones, a comprehensive assessment is required to establish the accuracy of digital bone reconstructions from three-dimensional (3D) photogrammetry. Five human bones (femur, radius, scapula, vertebra, patella) were marked with pencil, to establish between 9 and 29 landmarks. The distances between landmarks were measured from the physical bones and digitized from 3D reconstructions. Images used for reconstructions were taken on two separate days, allowing for repeatability to be established. In comparison to physical measurements, the mean (±standard deviation) absolute differences were between 0.2±0.1mm and 0.4±0.2mm. The mean (±standard deviation) absolute differences between reconstructions were between 0.3±<0.1mm and 0.4±0.4mm. The 3D photogrammetry procedures described are accurate and repeatable, permitting quantitative analyses to be conducted from digital reconstructions. Moreover, 3D photogrammetry may be used to capture and preserve anatomical materials for anatomy education.

Effect of combined red and infrared wavelengths on inflammation, hemorrhage, and muscle damage caused by Bothrops leucurus snake venom.

To evaluate the effects of red and infrared wavelengths, separately and combined, on the inflammatory process and collagen deposition in muscle damage caused by B. leucurus venom. 112 mice were inoculated with diluted venom (0.6mg/kg) in the gastrocnemius muscle. The animals were divided into four groups: one control (CG) and three treatments, namely: 1) red laser (λ=660 nm) (RG), 2) infrared laser (λ=808 nm) (IG) and 3) red laser (λ=660 nm) + infrared (λ=808 nm) (RIG). Each group was subdivided into four subgroups, according to the duration of treatment application (applications every 24 hours over evaluation times of up to 144 hours). A diode laser was used (0.1 W, CW, 1J/point, ED: 10 J/cm2). Both wavelengths reduced the intensity of inflammation and the combination between them significantly intensified the anti-inflammatory response. Photobiomodulation also changed the type of inflammatory infiltrate observed and RIG had the highest percentage of mononuclear cells in relation to the other groups. Hemorrhage intensity was significantly lower in treated animals and RIG had the highest number of individuals in which this variable was classified as mild. As for collagen deposition, there was a significant increase in RG in relation to CG, in RIG in relation to CG and in RIG in relation to IG. Photobiomodulation proved to be effective in the treatment of inflammation and hemorrhage caused by B. leucurus venom and stimulated collagen deposition. Better results were obtained with the combined wavelengths.

Biofabrication of Living Actuators.

The impact of tissue engineering has extended beyond a traditional focus in medicine to the rapidly growing realm of biohybrid robotics. Leveraging living actuators as functional components in machines has been a central focus of this field, generating a range of compelling demonstrations of robots capable of muscle-powered swimming, walking, pumping, gripping, and even computation. In this review, we highlight key advances in fabricating tissue-scale cardiac and skeletal muscle actuators for a range of functional applications. We discuss areas for future growth including scalable manufacturing, integrated feedback control, and predictive modeling and also propose methods for ensuring inclusive and bioethics-focused pedagogy in this emerging discipline. We hope this review motivates the next generation of biomedical engineers to advance rational design and practical use of living machines for applications ranging from telesurgery to manufacturing to on- and off-world exploration.

Integrated impact of multiple body composition parameters on overall survival in gastrointestinal or genitourinary cancers: A descriptive cohort study.

BACKGROUND: This study aimed to evaluate if combining low muscle mass with additional body composition abnormalities, such as myosteatosis or adiposity, could improve survival prediction accuracy in a large cohort of gastrointestinal and genitourinary malignancies. METHODS: In total, 2015 patients with surgically-treated gastrointestinal or genitourinary cancer were retrospectively analyzed. Skeletal muscle index, skeletal muscle radiodensity, and visceral/subcutaneous adipose tissue index were determined. The primary outcome was overall survival determined by hospital records. Multivariate Cox hazard models were used to identify independent predictors for poor survival. C-statistics were assessed to quantify the prognostic capability of the models with or without incorporating body composition parameters. RESULTS: Survival curves were significantly demarcated by all 4 measures. Skeletal muscle radiodensity was associated with non-cancer-related deaths but not with cancer-specific survival. The survival outcome of patients with low skeletal muscle index was poor (5-year OS; 65.2%), especially when present in combination with low skeletal muscle radiodensity (5-year overall survival; 50.2%). All examined body composition parameters were independent predictors of lower overall survival. The model for predicting overall survival without incorporating body composition parameters had a c-index of 0.68 but increased to 0.71 with the inclusion of low skeletal muscle index and 0.72 when incorporating both low skeletal muscle index and low skeletal muscle radiodensity/visceral adipose tissue index/subcutaneous adipose tissue index. CONCLUSION: Patients exhibiting both low skeletal muscle index and other body composition abnormalities, particularly low skeletal muscle radiodensity, had poorer overall survival. Models incorporating multiple body composition prove valuable for mortality prediction in oncology settings.

Thrombospondin-1 promotes fibro-adipogenic stromal expansion and contractile dysfunction of the diaphragm in obesity.

Pulmonary disorders impact 40% to 80% of individuals with obesity. Respiratory muscle dysfunction is linked to these conditions; however, its pathophysiology remains largely undefined. Mice subjected to diet-induced obesity (DIO) develop diaphragmatic weakness. Increased intra-diaphragmatic adiposity and extracellular matrix (ECM) content correlate with reductions in contractile force. Thrombospondin-1 (THBS1) is an obesity-associated matricellular protein linked with muscular damage in genetic myopathies. THBS1 induces proliferation of fibro-adipogenic progenitors (FAPs) - mesenchymal cells that differentiate into adipocytes and fibroblasts. We hypothesized that THBS1 drives FAP-mediated diaphragm remodeling and contractile dysfunction in DIO. We tested this by comparing the effects of dietary challenge on diaphragms of wild-type (WT) and Thbs1 knockout (Thbs1-/-) mice. Bulk and single-cell transcriptomics demonstrated DIO-induced stromal expansion in WT diaphragms. Diaphragm FAPs displayed upregulation of ECM and TGF ß-related expression signatures and augmentation of a Thy1-expressing sub-population previously linked to type 2 diabetes. Despite similar weight gain, Thbs1-/- mice were protected from these transcriptomic changes and from obesity-induced increases in diaphragm adiposity and ECM deposition. Unlike WT controls, Thbs1-/- diaphragms maintained normal contractile force and motion after DIO challenge. These findings establish THBS1 as a necessary mediator of diaphragm stromal remodeling and contractile dysfunction in overnutrition and a potential therapeutic target in obesity-associated respiratory dysfunction.

Rate of skin and nerve complications as a result of cutaneous traction with modern foam boots.

INTRODUCTION: Cutaneous traction is used to temporize lower extremity fractures and relies on friction between the skin and surrounding material to apply a longitudinal force. This circumferential compressive force can lead to pressure sores, skin sloughing, or compressive neuropathies. These complications have been reported in up to 11% of patients when the cutaneous traction relies on adhesive tapes, plaster, and rubber bandages being in immediate contact with the skin. The rates of these complications are not well documented when using modern foam boots. METHODS: A retrospective chart review was performed on all orthopedic trauma patients who suffered pelvic or lower extremity injuries between March 1st, 2020 and April 30th, 2021 at a single Level-1 trauma center. We included all patients with femoral fractures, axially unstable pelvic ring and/or acetabular fractures, and unstable hip dislocations temporized with the use of cutaneous traction. All patients had intact skin and lower extremity nerve function prior to application. RESULTS: There were 138 patients identified with 141 lower extremities. The average patient age was 50.7 (6-100) years. Mean traction weight of 9.8 (5-20) pounds. Average traction duration was 20.9 (2.3-243.5) hours. At the time of traction removal, there was 1 (0.7%) new skin wound and 0 nerve palsies. The new skin wound was a stage one heel pressure sore and did not require further treatment. CONCLUSION: Cutaneous traction with a modern foam boot was found to have a skin complication rate of 0.7% and a nerve palsy complication rate of 0% for an overall complication rate of 0.7%, which has not been previously established and is lower than historically reported complication rates of 11% when utilizing adhesive and plaster directly on skin. Foam boot Cutaneous traction may be considered a safe option for traction placement.

The impact of aerobic exercise timing on BMAL1 protein expression and antioxidant responses in skeletal muscle of mice.

It is well known that the adaptations of muscular antioxidant system to aerobic exercise depend on the frequency, intensity, duration, type of the exercise. Nonetheless, the timing of aerobic exercise, related to circadian rhythms or biological clock, may also affect the antioxidant defense system, but its impact remains uncertain. Bain and muscle ARNT-like 1 (BMAL1) is the core orchestrator of molecular clock, which can maintain cellular redox homeostasis by directly controlling the transcriptional activity of nuclear factor erythroid 2-related factor 2 (NRF2). So, our research objective was to evaluate the impacts of aerobic exercise training at various time points of the day on BMAL1 and NRF2-mediated antioxidant system in skeletal muscle. C57BL/6J mice were assigned to the control group, the group exercising at Zeitgeber Time 12 (ZT12), and the group exercising at ZT24. Control mice were not intervened, while ZT12 and ZT24 mice were trained for four weeks at the early and late time point of their active phase, respectively. We observed that the skeletal muscle of ZT12 mice exhibited higher total antioxidant capacity and lower reactive oxygen species compared to ZT24 mice. Furthermore, ZT12 mice improved the colocalization of BMAL1 with nucleus, the protein expression of BMAL1, NRF2, NAD(P)H quinone oxidoreductase 1, heme oxygenase 1, glutamate-cysteine ligase modifier subunit and glutathione reductase in comparison to those of ZT24 mice. In conclusion, the 4-week aerobic training performed at ZT12 is more effective for enhancing NRF2-mediated antioxidant responses of skeletal muscle, which may be attributed to the specific activation of BMAL1.

Increased prevalence of the null allele of the p.Arg577Ter variant in the ACTN3 gene in Brazilian long-distance athletes: A retrospective study.

INTRODUCTION: The phenotypic consequences of the p.Arg577Ter variant in the α-actinin-3 (ACTN3) gene are suggestive of a trade-off between performance traits for speed and endurance sports. Although there is a consistent association of the c.1729C allele (aka R allele) with strength/power traits, there is still a debate on whether the null allele (c.1729T allele; aka X allele) influences endurance performance. The present study aimed to test the association of the ACTN3 p.Arg577Ter variant with long-distance endurance athlete status, using previously published data with the Brazilian population. METHODS: Genotypic data from 203 long-distance athletes and 1724 controls were analysed in a case-control approach. RESULTS: The frequency of the X allele was significantly higher in long-distance athletes than in the control group (51.5% vs. 41.4%; p = 0.000095). The R/X and X/X genotypes were overrepresented in the athlete group. Individuals with the R/X genotype instead of the R/R genotype had a 1.6 increase in the odds of being a long-distance athlete (p = 0.012), whereas individuals with the X/X genotype instead of the R/R genotype had a 2.2 increase in the odds of being a long-distance athlete (p = 0.00017). CONCLUSION: The X allele, mainly the X/X genotype, was associated with long-distance athlete status in Brazilians.

Isolation of Mitochondria from Murine Skeletal Muscle.

Skeletal muscle is one of the largest tissues in human body. Besides enabling voluntary movements and maintaining body's metabolic homeostasis, skeletal muscle is also a target of many pathological conditions. Mitochondria occupy 10-15% volume of a muscle myofiber and regulate many cellular processes, which often determine the fate of the cell. Isolation of mitochondria from skeletal muscle provides opportunities for various multi-omics studies with a focus on mitochondria in biomedical research field. Here we describe a protocol to efficiently isolate mitochondria with high quality and purity from skeletal muscle of mice using Nycodenz density gradient ultracentrifugation.