Tenascin-C-enriched regeneration-specific extracellular matrix guarantees superior muscle regeneration in Ambystoma mexicanum.

Severe muscle injury causes distress and difficulty in humans. Studying the high regenerative ability of the axolotls may provide hints for the development of an effective treatment for severe injuries to muscle tissue. Here, we examined the regenerative process in response to a muscle injury in axolotls. We found that axolotls are capable of complete regeneration in response to a partial muscle resection called volumetric muscle loss (VML), which mammals cannot perfectly regenerate. We investigated the mechanisms underlying this high regenerative capacity in response to VML, focusing on the migration of muscle satellite cells and the extracellular matrix (ECM) formed during VML injury. Axolotls form tenascin-C (TN-C)-enriched ECM after VML injury. This TN-C-enriched ECM promotes the satellite cell migration. We confirmed the importance of TN-C in successful axolotl muscle regeneration by creating TN-C mutant animals. Our results suggest that the maintenance of a TN-C-enriched ECM environment after muscle injury promotes the release of muscle satellite cells and supports eventually high muscle regenerative capacity. In the future, better muscle regeneration may be achieved in mammals through the maintenance of TN-C expression.

Cinnamaldehyde attenuates TNF-α induced skeletal muscle loss in C2C12 myotubes via regulation of protein synthesis, proteolysis, oxidative stress and inflammation.

Inflammation is the primary driver of skeletal muscle wasting, with oxidative stress serving as both a major consequence and a contributor to its deleterious effects. In this regard, regulation of both can efficiently prevent atrophy and thus will increase the rate of survival [1]. With this idea, we hypothesize that preincubation of Cinnamaldehyde (CNA), a known compound with anti-oxidative and anti-inflammatory properties, may be able to prevent skeletal muscle loss. To examine the same, C2C12 post-differentiated myotubes were treated with 25 ng/ml Tumor necrosis factor-alpha (TNF-α) in the presence or absence of 50 µM CNA. The data showed that TNF-α mediated myotube thinning and a lower fusion index were prevented by CNA supplementation 4 h before TNF-α treatment. Moreover, a lower level of ROS and thus maintained antioxidant defense system further underlines the antioxidative function of CNA in atrophic conditions. CNA preincubation also inhibited an increase in the level of inflammatory cytokines and thus led to a lower level of inflammation even in the presence of TNF-α. With decreased oxidative stress and inflammation by CNA, it was able to maintain the intracellular level of injury markers (CK, LDH) and SDH activity of mitochondria. In addition, CNA modulates all five proteolytic systems [cathepsin-L, UPS (atrogin-1), calpain, LC3, beclin] simultaneously with an upregulation of Akt/mTOR pathway, in turn, preserves the muscle-specific proteins (MHCf) from degradation by TNF-α. Altogether, our study exhibits attenuation of muscle loss and provides insight into the possible mechanism of action of CNA in curbing TNF-α induced muscle loss, specifically its effect on proteolysis and protein synthesis.

Kcnma1 is involved in mitochondrial homeostasis in diabetes-related skeletal muscle atrophy.

Uncontrolled diabetes causes a catabolic state with multi-organic complications, of which impairment on skeletal muscle contributes to the damaged mobility. Kcnma1 gene encodes the pore-forming α-subunit of Ca2+ - and voltage-gated K+ channels of large conductance (BK channels), and loss-of-function mutations in Kcnma1 are in regards to impaired myogenesis. Herein, we observed a time-course reduction of Kcnma1 expression in the tibialis anterior muscles of leptin receptor-deficient (db/db) diabetic mice. To investigate the role of Kcnma1 in diabetic muscle atrophy, muscle-specific knockdown of Kcnma1 was achieved by mice receiving intravenous injection of adeno-associated virus-9 (AAV9)-encoding shRNA against Kcnma1 under the muscle creatine kinase (MCK) promoter. Impairment on muscle mass and myogenesis were observed in m/m mice with AAV9-shKcnma1 intervention, while this impairment was more obvious in diabetic db/db mice. Simultaneously, damaged mitochondrial dynamics and biogenesis showed much severer in db/db mice with AAV9-shKcnma1 intervention. RNA sequencing revealed the large transcriptomic changes resulted by Kcnma1 knockdown, and changes in mitochondrial homeostasis-related genes were validated. Besides, the artificial alteration of Kcnma1 in mouse C2C12 myoblasts was achieved with an adenovirus vector. Consistent results were demonstrated by Kcnma1 knockdown in palmitate-treated cells, whereas opposite results were exhibited by Kcnma1 overexpression. Collectively, we document Kcnma1 as a potential keeper of mitochondrial homeostasis, and the loss of Kcnma1 is a critical event in priming skeletal muscle loss in diabetes.

Skeletal muscle mass and function are affected by pancreatic atrophy, pancreatic exocrine insufficiency and poor nutritional status in patients with chronic pancreatitis.

BACKGROUND/OBJECTIVE: Previous studies have demonstrated that sarcopenia is frequently observed in patients with chronic pancreatitis (CP). However, most studies have defined sarcopenia solely based on skeletal muscle (SM) loss, and muscle weakness such as grip strength (GS) reduction has not been considered. We aimed to clarify whether SM loss and reduced GS have different associations with clinical characteristics and pancreatic imaging findings in patients with CP. METHODS: One hundred two patients with CP were enrolled. We defined SM loss by the SM index at the third lumbar vertebra on CT (<42 cm2/m2 for males and <38 cm2/m2 for females), and reduced GS by < 28 kg for males and <18 kg for females. RESULTS: Fifty-seven (55.9 %) patients had SM loss, 21 (20.6 %) had reduced GS, and 17 (16.7 %) had both. Patients with SM loss had lower body mass index, weaker GS, higher Controlling Nutritional Status score, lower serum lipase level, and lower urinary para-aminobenzoic acid excretion rate, suggesting worse nutritional status and pancreatic exocrine insufficiency. On CT, main pancreatic duct dilatation and parenchymal atrophy were more frequent in patients with SM loss than in those without it. Patients with reduced GS were older and had worse nutritional status than those without it. CONCLUSIONS: SM loss was associated with pancreatic exocrine insufficiency, low nutritional status, and pancreatic imaging findings such as parenchymal atrophy and main pancreatic duct dilatation, whereas older age and low nutritional status led to additional reduced GS.

Cholinesterase as a predictor of skeletal muscle loss after gastrectomy for gastric cancer.

BACKGROUND: Cholinesterase is a classical nutritional and inflammatory marker. The aim of the present study was to evaluate the value of cholinesterase as a predictive marker for postoperative skeletal muscle loss after gastrectomy for gastric cancer. METHODS: The study comprised 68 patients who had undergone gastrectomy for gastric cancer. Skeletal muscle mass was evaluated using skeletal mass index, and major skeletal muscle loss was defined as less than or equal to the median change rate (1-year postoperative/preoperative) of skeletal mass index in all patients. We explored the relationship between postoperative major skeletal muscle loss and disease-free survival and overall survival. Then we investigated the relationship between change rate of skeletal muscle index and serum cholinesterase levels after gastrectomy. RESULTS: The median value of change rate of skeletal mass index was 0.93. Postoperative major skeletal muscle loss was significantly associated with disease-free survival after gastrectomy (P = 0.003). Although major skeletal muscle loss had worse overall survival, it was not significant (P = 0.058). The change rate of skeletal mass index and cholinesterase had a stronger positive correlation compared with other nutritional indices according to Spearman's rank correlation coefficient (r = 0.438, P ≤ 0.001). CONCLUSION: Evaluation of serum cholinesterase levels may be valuable for predicting postoperative skeletal muscle loss after gastrectomy, suggesting the importance of cholinesterase in postoperative nutritional management of patients with gastric cancer.

Muscle loss phenotype in COPD is associated with adverse outcomes in the UK Biobank.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disorder with systemic consequences that can cause a muscle loss phenotype (MLP), which is characterized by the loss of muscle mass, muscle strength, or loss of both muscle and fat mass. There are limited data comparing the individual traits of MLP with clinical outcomes in a large unbiased cohort of COPD patients. Our aim was to determine the proportion of patients who met criteria for MLP in an unbiased sample of COPD patients at the population-level. We also determined if specific MLP features were associated with all-cause and COPD-related mortality. METHODS: A retrospective population-based cohort analysis of the UK Biobank was performed. COPD was defined by a FEV1/FVC ratio < 0.7, physician established diagnosis of COPD, or those with a COPD-related hospitalization before baseline assessment. MLP included one or more of the following: 1) Low fat-free mass index (FFMI) on bioelectric impedance analysis (BIA) or 2) Appendicular skeletal muscle index (ASMI) on BIA, 3) Low muscle strength defined by handgrip strength (HGS), or 4) Low muscle and fat mass based on body mass index (BMI). Cox regression was used to determine the association between MLP and all-cause or COPD-related mortality. All models were adjusted for sex, age at assessment, ethnicity, BMI, alcohol use, smoking status, prior cancer diagnosis and FEV1/FVC ratio. RESULTS: There were 55,782 subjects (56% male) with COPD followed for a median of 70.1 months with a mean(± SD) age at assessment of 59 ± 7.5 years, and FEV1% of 79.2 ± 18.5. Most subjects had mild (50.4%) or moderate (42.8%) COPD. Many patients had evidence of a MLP, which was present in 53.4% of COPD patients (34% by ASMI, 26% by HGS). Of the 5,608 deaths in patients diagnosed with COPD, 907 were COPD-related. After multivariate adjustment, COPD subjects with MLP had a 30% higher hazard-ratio for all-cause death and 70% higher hazard-ratio for COPD-related death. CONCLUSIONS: Evidence of MLP is common in a large population-based cohort of COPD and is associated with higher risk for all-cause and COPD-related mortality.

Changes in Bone Mineral Density in Patients With Non-dialysis-Dependent Chronic Kidney Disease Are Associated With Body Composition.

OBJECTIVE: Chronic kidney disease (CKD) and low bone mineral density (BMD) are highly prevalent and can co-exist. Parameters of mineral metabolism are associated with BMD in CKD, but other contributing factors may contribute. The aim of this study was to assess changes in BMD and its determinants in patients with nondialysis-dependent CKD (NDD-CKD). METHODS: Body composition and biochemical profiles were assessed in a retrospective hospital-based cohort study of patients with NDD-CKD. BMD, lean soft tissue (LST), appendicular LST (ALST), and percentage fat mass were assessed by dual-energy X-ray absorptiometry. The ALST index (ALSTI, ALST/height2) and load-capacity index (LCI, fat mass/LST) were calculated. Low BMD was defined as T-score ≤ -1.0. RESULTS: The mean time between assessments was 2.8 ± 1.3 years; 46 patients were included. A reduction in renal function was observed. Changes in body composition included reductions in ALST (P = .031), ALSTI (P = .021), a trend for BMD (P = .053), and an increase in percentage fat mass (P = .044) and LCI (P = .032). Females had a reduction in BMD (P = .034), ALST (P = .026), and ALSTI (P = .037). Patients with low BMD at baseline had lower LST (P = .013), ALST (P = .023), and percentage fat mass (P = .037) than those with normal BMD. Additionally, reductions in LST (P = .041), ALST (P = .006), and ALSTI (P = .008) were observed in patients who had low BMD at baseline, while no significant changes in body composition were observed in those with normal BMD at baseline. The following body composition parameters at baseline were determinants of BMD status at follow-up: LST (odds ratio [OR]: 0.899, 95% confidence interval [CI]: 0.829-0.976, P = .010), ALST (OR: 0.825, 95% CI: 0.704-0.967, P = .017), and ALSTI (OR: 0.586, 95% CI: 0.354-0.968, P = .037), independent of fat mass and LCI. CONCLUSIONS: Detrimental body composition changes were observed without changes in body weight; these were more significant in females. Moreover, this is the first longitudinal study showing a protective effect of LST against BMD loss in patients with NDD-CKD.

Myogenic microRNAs as Therapeutic Targets for Skeletal Muscle Mass Wasting in Breast Cancer Models.

Breast cancer is the type of cancer with the highest prevalence in women worldwide. Skeletal muscle atrophy is an important prognostic factor in women diagnosed with breast cancer. This atrophy stems from disrupted skeletal muscle homeostasis, triggered by diminished anabolic signalling and heightened inflammatory conditions, culminating in an upregulation of skeletal muscle proteolysis gene expression. The importance of delving into research on modulators of skeletal muscle atrophy, such as microRNAs (miRNAs), which play a crucial role in regulating cellular signalling pathways involved in skeletal muscle protein synthesis and degradation, has been recognised. This holds true for conditions of homeostasis as well as pathologies like cancer. However, the determination of specific miRNAs that modulate skeletal muscle atrophy in breast cancer conditions has not yet been explored. In this narrative review, we aim to identify miRNAs that could directly or indirectly influence skeletal muscle atrophy in breast cancer models to gain an updated perspective on potential therapeutic targets that could be modulated through resistance exercise training, aiming to mitigate the loss of skeletal muscle mass in breast cancer patients.

Engineering skeletal muscle: Building complexity to achieve functionality.

Volumetric muscle loss (VML) VML is defined as the loss of a critical mass of skeletal muscle that overwhelms the muscle's natural healing mechanisms, leaving patients with permanent functional deficits and deformity. The treatment of these defects is complex, as skeletal muscle is a composite structure that relies closely on the action of supporting tissues such as tendons, vasculature, nerves, and bone. The gold standard of treatment for VML injuries, an autologous muscle flap transfer, suffers from many shortcomings but nevertheless remains the best clinically available avenue to restore function. This review will consider the use of composite tissue engineered constructs, with multiple components that act together to replicate the function of an intact muscle, as an alternative to autologous muscle flaps. We will discuss recent advances in the field of tissue engineering that enable skeletal muscle constructs to more closely reproduce the functionality of an autologous muscle flap by incorporating vasculature, promoting innervation, and reconstructing the muscle-tendon boundary. Additionally, our understanding of the cellular composition of skeletal muscle has evolved to recognize the importance of a diverse variety of cell types in muscle regeneration, including fibro/adipogenic progenitors and immune cells like macrophages and regulatory T cells. We will address recent advances in our understanding of how these cell types interact with, and can be incorporated into, implanted tissue engineered constructs.

Combined application of biosponges and an antifibrotic agent for the treatment of volumetric muscle loss.

Volumetric muscle loss (VML) causes irrecoverable loss of muscle mass and strength and results in permanent disability. VML injury shows extensive fibrosis, which impedes functional tissue regeneration. Our lab has created a biosponge scaffold composed of extracellular matrix (ECM) proteins (i.e., biosponge) that can enhance muscle regeneration and function following VML. In this work, a potent small molecule inhibitor of alpha v-subunit containing integrins known as IDL-2965 was incorporated into the biosponges for localized suppression of fibrosis post-VML. Our results demonstrate that local delivery of IDL-2965 via the biosponges attenuated the deposition of fibrotic tissue preceded by a downregulation of profibrotic genes in VML-injured muscles. The reduction in fibrotic tissue had no detrimental effects on muscle mass, function, size, or vascularity. Overall, these findings suggest that the codelivery of biosponges and IDL-2965 is a safe and effective strategy for the mitigation of fibrotic tissue deposition in VML-injured muscles.

Artificial Intelligence Optical Biopsy for Evaluating the Functional State of Wounds.

INTRODUCTION: The clinical characterization of the functional status of active wounds in terms of their driving cellular and molecular biology remains a considerable challenge that currently requires excision via a tissue biopsy. In this pilot study, we use convolutional Siamese neural network (SNN) architecture to predict the functional state of a wound using digital photographs of wounds in a canine model of volumetric muscle loss (VML). METHODS: Digital images of VML injuries and tissue biopsies were obtained in a standardized fashion from an established canine model of VML. Gene expression profiles for each biopsy site were obtained using RNA sequencing. These profiles were converted to functional profiles by a manual review of validated gene ontology databases in which we determined a hierarchical representation of gene functions based on functional specificity. An SNN was trained to regress functional profile expression values, informed by an image segment showing the surface of a small tissue biopsy. RESULTS: The SNN was able to predict the functional expression of a range of functions based with error ranging from ∼5% to ∼30%, with functions that are most closely associated with the early state of wound healing to be those best-predicted. CONCLUSIONS: These initial results suggest promise for further research regarding this novel use of machine learning regression on medical images. The regression of functional profiles, as opposed to specific genes, both addresses the challenge of genetic redundancy and gives a deeper insight into the mechanistic configuration of a region of tissue in wounds.

Higher dietary protein intake is associated with sarcopenia in older British twins.

BACKGROUND: Sarcopenia, characterised by an accelerated loss of skeletal muscle mass and function, is associated with negative outcomes. This study aimed to evaluate factors associated with skeletal muscle strength, mass and sarcopenia, particularly protein intake, and to assess whether shared twin characteristics are important. METHODS: This study utilised cross-sectional data from a study of community-dwelling twins aged ≥60 years. Multivariable logistic regression and between- and within-twin pair regression modelling were used. RESULTS: Participants (n = 3,302) were 89% female (n = 2,923), aged a mean of 72.1 (±7.3) years and composed of 858 (55%) monozygotic, 709 (45%) dizygotic twin pairs and 168 individual lone twins. Using optimal protein intake as the reference group (1.0-1.3 g/kg/day), there was no significant association between protein intake (neither high nor low) and low muscle strength, or between low protein intake and sarcopenia (odds ratio (OR) 0.7; 95% confidence interval (CI) 0.39-1.25; P = 0.229) in unadjusted models. High protein intake (>1.3 g/kg/day) was associated with low muscle mass (OR 1.76; 95% CI 1.39-2.24; P < 0.0001), while low protein intake was protective (OR 0.52; 95% CI 0.40-0.67; P < 0.0001). High protein intake was associated with sarcopenia (OR 2.04; 95% CI 1.21-3.44; P = 0.008), and this was robust to adjustment for demographic, anthropometric and dietary factors. The association between muscle strength and weight, body mass index, healthy eating index, protein intake and alpha diversity was not significantly influenced by shared twin factors, indicating greater amenability to interventions. CONCLUSIONS: High protein intake is associated with sarcopenia in a cohort of healthy older twins.

Transcriptome profiling of a synergistic volumetric muscle loss repair strategy.

Volumetric muscle loss overwhelms skeletal muscle's ordinarily capable regenerative machinery, resulting in severe functional deficits that have defied clinical repair strategies. In this manuscript we pair the early in vivo functional response induced by differing volumetric muscle loss tissue engineering repair strategies that are broadly representative of those explored by the field (scaffold alone, cells alone, or scaffold + cells) to the transcriptomic response induced by each intervention. We demonstrate that an implant strategy comprising allogeneic decellularized skeletal muscle scaffolds seeded with autologous minced muscle cellular paste (scaffold + cells) mediates a pattern of increased expression for several genes known to play roles in axon guidance and peripheral neuroregeneration, as well as several other key genes related to inflammation, phagocytosis, and extracellular matrix regulation. The upregulation of several key genes in the presence of both implant components suggests a unique synergy between scaffolding and cells in the early period following intervention that is not seen when either scaffolds or cells are used in isolation; a finding that invites further exploration of the interactions that could have a positive impact on the treatment of volumetric muscle loss.

Presence of Sarcopenia before Kidney Transplantation Is Associated with Poor Outcomes.

INTRODUCTION: Kidney transplantation is the treatment of choice for patients with renal failure. It is crucial to select which patients may benefit from renal transplantation and which are at high risk for post-transplant complications. Sarcopenia is associated with poor outcome in various conditions, including in chronic kidney disease patients. The gold standard for measuring sarcopenia is computed tomography (CT) imaging to estimate muscle mass and quality since it is objective, reproducible, and reflects the overall health condition. The data regarding those measurements among kidney transplant recipients are limited, therefore we aimed to describe it in patients before kidney transplantation, assess the parameters associated with sarcopenia, and evaluate the clinical significance of those markers on outcomes following transplantation. METHODS: We retrospectively analyzed 183 kidney transplant recipients who had a CT scan 90 days prior to transplant. Sarcopenia was assessed by measuring the cross-sectional area (CSA) and mean muscle density of the psoas muscle at the third and fourth lumbar vertebrae levels and paravertebral muscles at the 12th thoracic vertebra level. RESULTS: There was a strong linear correlation between muscle size measured as CSA of the psoas muscle at the L3 and L4 vertebral body level and the CSA of the paravertebral muscles at the D12 vertebra level, and a moderate correlation to muscle density at those levels. Age was independently associated with risk of sarcopenia, defined as psoas CSA in the lowest tertile, with every year of age increasing the risk by 5%. CSA at the L3 level had a significant independent association with post kidney transplantation mortality, with an adjusted hazard ratio of 0.86 per cm2. There was a significantly longer hospitalization period postoperation in kidney recipients in the lower tertile of psoas CSA and density. CONCLUSIONS: Sarcopenia as measured by psoas CSA is associated with poor short- and long-term outcomes following kidney transplantation and should be included as part of the assessment of kidney transplantation candidates.

Optical Biopsy Using a Neural Network to Predict Gene Expression From Photos of Wounds.

BACKGROUND: The clinical characterization of the biological status of complex wounds remains a considerable challenge. Digital photography provides a non-invasive means of obtaining wound information and is currently employed to assess wounds qualitatively. Advances in machine learning (ML) image processing provide a means of identifying "hidden" features in pictures. This pilot study trains a convolutional neural network (CNN) to predict gene expression based on digital photographs of wounds in a canine model of volumetric muscle loss (VML). MATERIALS AND METHODS: Images of volumetric muscle loss injuries and tissue biopsies were obtained in a canine model of VML. A CNN was trained to regress gene expression values as a function of the extracted image segment (color and spatial distribution). Performance of the CNN was assessed in a held-back test set of images using Mean Absolute Percentage Error (MAPE). RESULTS: The CNN was able to predict the gene expression of certain genes based on digital images, with a MAPE ranging from ∼10% to ∼30%, indicating the presence and identification of distinct, and identifiable patterns in gene expression throughout the wound. CONCLUSIONS: These initial results suggest promise for further research regarding this novel use of ML regression on medical images. Specifically, the use of CNNs to determine the mechanistic biological state of a VML wound could aid both the design of future mechanistic interventions and the design of trials to test those therapies. Future work will expand the CNN training and/or test set, with potential expansion to predicting functional gene modules.

Effect of skeletal muscle loss during neoadjuvant imatinib therapy on clinical outcomes in patients with locally advanced GIST.

BACKGROUND: Currently, the effect of skeletal muscle loss during neoadjuvant imatinib therapy on clinical outcomes in patients with locally advanced gastrointestinal stromal tumors (LA-GIST) remains unclear. This study aims to investigate the relationship between changes in skeletal muscle and postoperative complications, survival and tumor response in patients with LA-GIST during neoadjuvant therapy with imatinib. METHODS: We retrospectively analyzed pre- and post-treatment computed tomography images of 57 GIST patients who underwent radical surgery after neoadjuvant therapy with imatinib from January 2013 to March 2019. Skeletal muscle index (SMI) was measured at the L3 vertebral level in all patients. A cut-off value (SMI < 52.3 cm2/m2 and < 38.6 cm2/m2 for men and women, respectively) published in a previous study was used to define sarcopenia. Based on gender, we defined ΔSMI (%)/250 days above 9.69% for men and ΔSMI (%)/250 days above 7.63% for women as significant muscle loss (SML). Factors associated with postoperative complications and tumor response were analyzed using logistic regression, and predictors affecting patient prognosis were analyzed using Cox regression. RESULTS: Of the 57 patients, sarcopenia was present before and after neoadjuvant therapy in 20 (35.09%) and 28 (49.12%) patients, respectively. It was not associated with immediate or long-term clinical outcomes. However, patients with SML during neoadjuvant therapy had a higher incidence of postoperative complications (60.00% vs. 25.00%, p = 0.008), worse pathological regression (44.00% vs. 75.00%, p = 0.017) and worse 3-year survival (Male, 68.75% vs. 95.45%, p = 0.027; Female, 66.67% vs. 100.00%, p = 0.046) than patients without SML. CONCLUSION: The development of SML during neoadjuvant therapy in LA-GIST patients, rather than pre- and post-treatment sarcopenia, is a major prognostic factor for the long-term prognosis and is also associated with recent postoperative complication rates and pathological regression.

Evaluation of the Therapeutic Potential of Human iPSCs in a Murine Model of VML.

Volumetric muscle loss injury is a common health problem with long-term disabilities. One common treatment is using muscle flaps from donor site, which has limited potentials due to donor site availability and morbidity. Although several stem cell therapies have been evaluated so far, most suffer from limited availability, immune incompatibility, or differentiation potential. Therefore, induced pluripotent stem cells (iPSCs) have a great promise for this purpose due to their unique differentiation, self-renewal, and immunocompatibility. Current study was designed to determine therapeutic potential of human iPSCs (hiPSCs) in a mouse model of volumetric muscle loss. Muscles were subjected to excision to generate 30%-40% muscle loss. Next, hiPSCs were differentiated toward skeletal myogenic progenitors and used with fibrin hydrogel to reconstruct the lost muscle. Histologic evaluation of the treated muscles indicated abundant engraftment of donor-derived mature fibers expressing human markers. Donor-derived fibers were also positive for the presence of neuromuscular junction (NMJ), indicating their proper innervation. Evaluation of the engrafted region indicated the presence of donor-derived satellite cells expressing human markers and Pax7. Finally, in situ muscle function analysis demonstrated significant improvement of the muscle contractility in muscles treated with hiPSCs. These results therefore provide key evidence for the therapeutic potential of human iPSCs in volumetric muscle loss injuries.

Total iron binding capacity is a predictor for muscle loss in maintenance hemodialysis patients.

BACKGROUND: Protein-energy wasting in hemodialysis (HD) patients is characterized by decreased skeletal muscle mass and plasma protein. Some previous studies reported relationships between skeletal muscle dysfunction and iron deficiency. Dialysis patients with malnutrition may have a functional iron deficiency (FID) because of inflammation. Serum total iron binding capacity (TIBC), correlated with transferrin, is a nutritional status marker in HD patients and a biomarker of iron status. The relationship between muscle loss and iron status is unknown. The aim of the present study was to assess the relationship between iron status and change in skeletal muscle mass. METHODS: A prospective cohort of 267 HD patients was examined for 12 months. Blood samples were obtained at baseline to measure TIBC, ferritin, transferrin saturation (TSAT), and hepcidin-25. Nutritional status and changes in muscle mass were assessed by subjective global assessment, albumin, creatinine index, and percentage creatinine generation rate. RESULTS: At baseline, lower tertiles of TIBC were significantly related to lower muscle mass and albumin levels; they were also significantly correlated with high ferritin, hepcidin-25, and TSAT levels, as well as a higher proportion of use of erythropoiesis-stimulating agents. Multiple regression analysis adjusted with confounders showed TIBC was an independent biomarker for decreased muscle mass and albumin. Change in muscle mass remained significantly decreased in the lower tertile of TIBC and in malnourished patients. CONCLUSIONS: The present study demonstrated relationships between FID and muscle loss. TIBC was an independent biomarker of muscle loss in HD patients, considering iron status, inflammation, oxidative stress, and malnutrition.

Laparoscopic liver resection is associated with less significant muscle loss than the conventional open approach.

BACKGROUND: Laparoscopic liver resections (LLR) have been shown a treatment approach comparable to open liver resections (OLR) in hepatocellular carcinoma (HCC). However, the influence of procedural type on body composition has not been investigated. The aim of the current study was to compare the degree of skeletal muscle loss between LLR and OLR for HCC. METHODS: By using propensity score matching (PSM) analysis, 64 pairs of patients were enrolled. The change of psoas muscle index (PMI) after the operation was compared between the matched patients in the LLR and OLR. Risk factors for significant muscle loss (defined as change in PMI > mean change minus one standard deviation) were further investigated by multivariate analysis. RESULTS: Among patients enrolled, there was no significant difference in baseline characteristics between the two groups. The PMI was significantly decreased in the OLR group (P = 0.003). There were also more patients in the OLR group who developed significant muscle loss after the operations (P = 0.008). Multivariate analysis revealed OLR (P = 0.023), type 2 diabetes mellitus, indocyanine green retention rate at 15 min (ICG-15) > 10%, and cancer stage ≧ 3 were independent risk factors for significant muscle loss. In addition, significant muscle loss was associated with early HCC recurrence (P = 0.006). Metabolomic analysis demonstrated that the urea cycle may be decreased in patients with significant muscle loss. CONCLUSION: LLR for HCC was associated with less significant muscle loss than OLR. Since significant muscle loss was a predictive factor for early tumor recurrence and associated with impaired liver metabolism, LLR may subsequently result in a more favorable outcome.

The type of gastrectomy affects skeletal muscle loss and the long-term outcomes of elderly patients with gastric cancer: a retrospective study using computed tomography images.

PURPOSE: Sarcopenia is common in elderly gastrectomized patients and a known risk factor for postoperative complications and poor overall survival. However, the long-term outcomes of skeletal muscle loss after gastrectomy and the differences in outcomes of different gastrectomy procedures remain unclear. METHODS: The subjects of this retrospective study were 136 patients who underwent various gastrectomy procedures for early gastric cancer, namely: total gastrectomy (TG; n = 20), proximal gastrectomy (PG; n = 16), distal gastrectomy (DG; n = 60), and pylorus-preserving gastrectomy (PPG; n = 40). Skeletal muscle volume (SMV), calculated as the skeletal muscle index (SMI), was measured using cross-sectional computed tomography (CT) scans preoperatively and then 1, 2, and 3 years after gastrectomy. RESULTS: Sarcopenia developed from 2 years onwards in all the patients who underwent TG. The SMI and sarcopenia prevalence after gastrectomy deteriorated over time. Multivariate analysis revealed that TG and PG were significant risk factors for skeletal muscle loss in postoperative years 1 and 3. A decrease in the SMI after TG or PG was most remarkable in elderly patients. CONCLUSIONS: The type of gastrectomy affects skeletal muscle loss in the long term. Elderly patients who undergo TG or PG are at high risk of severe skeletal muscle loss.