Clinical Impact of Skeletal Muscle Mass and Nutritional Status in Patients with Recurrent or Advanced Gastric Cancer Treated with Nivolumab.

INTRODUCTION: This study aimed to evaluate the clinical impact of skeletal muscle mass and nutritional status in gastric cancer patients treated with nivolumab monotherapy as late-line treatment. METHODS: We conducted a multi-institutional retrospective study of 90 gastric cancer patients who previously received anti-PD-1 therapy (nivolumab). On computed tomography images captured before nivolumab induction, the skeletal muscle index (SMI, cm2/m2) was defined as the erector muscle area (cm2) divided by the height (m) squared. Patients were divided into two groups: those with SMI-high (n = 45) and those with SMI-low (n = 45). Prognostic nutritional index (PNI) was also calculated before nivolumab induction. The associations of SMI and PNI with response rate (RR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety were analyzed. RESULTS: The cutoff values for SMI were determined as 13.45 for males and 10.41 for females. SMI-high was significantly associated with a higher RR (odds ratio = 12.36, p = 0.02) and DCR (odds ratio = 2.97, p = 0.02). Although not significant, PNI-high also tended to be associated with a higher RR. Multivariate analysis showed that SMI-high was independently associated with a higher RR and higher DCR in gastric cancer. Moreover, prognostic analyses revealed that SMI-high (log-rank test p = 0.008) and PNI-high (log-rank test p = 0.0008) were significantly associated with longer OS since nivolumab induction. SMI-high was also associated with longer PFS (log-rank test p = 0.03). There were no significant differences in immune-related adverse event between SMI-low and SMI-high. CONCLUSION: SMI and PNI were associated with nivolumab efficacy in gastric cancer patients. Management of skeletal muscle loss and nutritional status in gastric cancer patients who will receive nivolumab would be beneficial to enhance survival outcomes.

Risk Factors Associated With Perioperative Skeletal Muscle Loss in Patients With Colorectal Cancer.

BACKGROUND/AIM: Postoperative changes in body composition, especially loss of muscle mass, often occur in gastrointestinal cancer patients. Few studies have reported perioperative changes in the body composition of patients with colorectal cancer. Therefore, this study aimed at clarifying changes in body composition during the perioperative period and identifying risk factors for skeletal muscle mass loss in patients with colorectal cancer. PATIENTS AND METHODS: This prospective observational study included 148 patients who underwent robot- or laparoscopic-assisted surgery for colorectal cancer. RESULTS: The rate of change in body composition at discharge was -6.25% for body fat, with a higher rate of decrease than that for skeletal muscle mass (-3.30%; p=0.0006) and body water mass (-2.66%; p=0.0001). Similarly, even at one month postoperatively, body fat mass (-8.05%) was reduced at a greater rate than skeletal muscle mass (-2.02% p=0.0001) and body water mass (-1.33% p=0.0001).The site-specific percent change in limb skeletal and trunk muscle mass at discharge was the greatest in the lower extremities at -5.37%, but one month after surgery, the upper extremities had the greatest change at -4.44%. The Prognostic Nutritional Index (PNI) influenced skeletal muscle mass loss at discharge [odds ratio (OR)=2.6; 95% confidence interval (CI)=1.30-5.58], while diabetes (OR=4.1; 95%CI=1.40-12.43) and ileostomy (OR=6.7; 95%CI=1.45-31.11) influenced skeletal muscle loss one month postoperatively. CONCLUSION: Preoperative and postoperative nutritional guidance/intervention and body part-specific rehabilitation should be provided to prevent skeletal muscle mass loss in patients with low PNI, diabetes, and those undergoing ileostomy.

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.

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.

Prognostic impact of muscle mass loss in elderly patients with oesophageal cancer receiving neoadjuvant chemoradiation therapy.

BACKGROUND: We aimed to identify the impact of muscle mass on locally advanced oesophageal cancer (LAEC) in elderly patients receiving neoadjuvant chemoradiation therapy (NACRT). METHODS: We reviewed the medical records of 345 patients diagnosed with LAEC who underwent NACRT and surgery. Physical variables, including height, weight, skeletal muscle mass, and laboratory values, were obtained before and after NACRT. Body mass index (BMI, kg/m2), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and prognostic nutritional index (PNI) were calculated as height/(weight)2, ANC/ALC, platelet count/ALC, and (10 × albumin + 0.05 × ALC), respectively. The cutoff for low muscle mass was 43.0 cm2/m2 for BMI below 25 kg/m2 and 53.0 cm2/m2 for BMI 25 kg/m2 or higher. The skeletal muscle index (SMI) was defined as skeletal muscle area/(height)2 (cm2/m2). The ΔSMI (%/50 days) was defined as (SMI after NACRT - SMI before NACRT)/interval (days) × 50 (days) to compare changes over the same period. The excessive muscle loss (EML) group was defined as patients with ΔSMI ≤-10% following NACRT. An elderly patient was defined as aged ≥65 years. The primary outcome measure was overall survival (OS). RESULTS: During a median follow-up of 32.8 months (range, 2.0-176.2), 192 patients died, with a median OS of 50.2 months. Elderly patients did not show inferior OS (young vs. elderly, 57.7% vs. 54.0% at 3 years, P = 0.247). 71.0% and 87.2% of all patients had low muscle mass before and after NACRT, respectively, which was not associated with OS (P = 0.270 and P = 0.509, respectively). Inflammatory (NLR and PLR) and nutritional index (PNI) values or their changes did not correlate with OS. However, the EML group had worse OS (41.6% vs. 63.2% at 3 years, P < 0.0001). In the multivariate analysis, EML was also a significant prognostic factor for OS. In the subgroup analysis by age, EML was a strong prognostic factor for OS in the elderly group. The 3-year OS was 36.8% in the EML group and 64.9% in the non-EML group (P < 0.0001) in elderly patients, and 47.4% and 62.1% (P = 0.063) in the young patients. In multivariate analysis of each subgroup, EML remained prognostic only in the elderly group (P = 0.008). CONCLUSIONS: EML may be strongly associated with a deteriorated OS in elderly patients undergoing NACRT, followed by surgery for LAEC. The strategies for decreasing muscle loss in these patients should be investigated.

Therapeutic applications of biological macromolecules and scaffolds for skeletal muscle regeneration: A review.

Skeletal muscle (SM) mass and strength maintenance are important requirements for human well-being. SM regeneration to repair minor injuries depends upon the myogenic activities of muscle satellite (stem) cells. However, losses of regenerative properties following volumetric muscle loss or severe trauma or due to congenital muscular abnormalities are not self-restorable, and thus, these conditions have major healthcare implications and pose clinical challenges. In this context, tissue engineering based on different types of biomaterials and scaffolds provides an encouraging means of structural and functional SM reconstruction. In particular, biomimetic (able to transmit biological signals) and several porous scaffolds are rapidly evolving. Several biological macromolecules/biomaterials (collagen, gelatin, alginate, chitosan, and fibrin etc.) are being widely used for SM regeneration. However, available alternatives for SM regeneration must be redesigned to make them more user-friendly and economically feasible with longer shelf lives. This review aimed to explore the biological aspects of SM regeneration and the roles played by several biological macromolecules and scaffolds in SM regeneration in cases of volumetric muscle loss.

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.

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.

Therapeutic Myogenesis Induced by Ultrasound Exposure in a Volumetric Skeletal Muscle Loss Injury Model.

BACKGROUND: Low-intensity pulsed ultrasound (LIPUS) irradiation has been shown to induce various responses in different cells. It has been shown that LIPUS activates extracellular signal-regulated kinase 1/2 (ERK1/2) through integrin. PURPOSE: To study the effects of LIPUS on myogenic regulatory factors and other related myogenesis elements in a volumetric skeletal muscle loss injury model. STUDY DESIGN: Controlled laboratory study. METHODS: C57BL/6J mice were subjected to full-thickness muscle defect injury of the quadriceps and treated with direct application of LIPUS 20 min/d or non-LIPUS treatment (control) for 3, 7, and 14 days. LIPUS was also applied to C2C12 cells in culture in the presence of low and high doses of lipopolysaccharides. The expression levels of myogenic regulatory factors and the expression levels of myokine-related and angiogenic-related proteins of the control and LIPUS groups were analyzed. RESULTS: Muscle volume in the injury site was restored at day 14 with LIPUS treatment. Paired-box protein 7, myogenic factor 5, myogenin, and desmin expressions were significantly different between control and LIPUS groups at days 7 and 14. Myokine and angiogenic cytokine-related factors were significantly increased in the LIPUS group at day 3 and decreased with no significant difference between the groups by day 14. LIPUS induced different responses of myogenic regulatory factors in C2C12 cells with low and high doses of lipopolysaccharides. LIPUS promoted myogenesis through short-lived increase in interleukin-6 and heme oxygenase 1, together with activation of ERK1/2. CONCLUSION: LIPUS had a constant effect on the variables of tissue damage, from macrotrauma to microtrauma, leading to efficient muscle regeneration. CLINICAL RELEVANCE: The focus of therapeutic strategies with LIPUS has been not only for microvascular regeneration but also for skeletal muscle and related local tissue recovery from acute or chronic damage.

Risk Factor of Sarcopenia After Gastrectomy in Elderly Patients With Gastric Cancer.

BACKGROUND/AIM: Sarcopenia is a progressive and generalized muscle disorder correlated with an increased risk of adverse outcomes, including falls, fractures, physical disability and mortality. Moreover, sarcopenia is associated with short- and long-term outcomes after surgery in patients with gastrointestinal malignancies. Additionally, severe skeletal muscle loss after surgery reduces quality of life. In this study, we analyzed the perioperative risk factors for skeletal muscle loss after gastrectomy in elderly patients undergoing radical gastrectomy for gastric cancer. PATIENTS AND METHODS: In this case-control study, we enrolled patients aged ≥75 years who underwent radical gastrectomy for gastric cancer between January 2014 and December 2020 at our Institution. The psoas muscle index was used to assess skeletal muscle mass. They were divided into two groups-muscle depletion (D group) and no depletion (ND group)-depending on the ratio of skeletal muscle loss before and after gastrectomy. RESULTS: The D and ND groups comprised 34 and 41 patients, respectively. Univariate analysis showed that open gastrectomy was a potential risk factor for postoperative skeletal muscle loss in elderly gastric cancer patients (p=0.017). In multiple logistic regression analysis using the following variables: sex, operation and approach, the D group had a significantly higher proportion of patients who underwent open surgery than the ND group (p=0.032). CONCLUSION: Open gastrectomy is an independent risk factor for the progression of sarcopenia after gastrectomy in elderly patients with gastric cancer. Laparoscopic surgery is an eligible method for preserving skeletal muscle mass in elderly patients with gastric cancer.

A Comparative Biochemical Study Between L-Carnosine and ß-Alanine in Amelioration of Hypobaric Hypoxia-Induced Skeletal Muscle Protein Loss.

Rathor, Richa, Sukanya Srivastava, and Geetha Suryakumar. A comparative biochemical study between L-carnosine and ß-alanine in amelioration of hypobaric hypoxia-induced skeletal muscle protein loss. High Alt Med Biol. 24:302-311, 2023. Background: Carnosine (CAR; ß-alanyl-L-histidine), a biologically active dipeptide is known for its unique pH-buffering capacity, metal chelating activity, and antioxidant and antiglycation property. ß-Alanine (ALA) is a nonessential amino acid and used to enhance performance and cognitive functions. Hypobaric hypoxia (HH)-induced muscle protein loss is regulated by multifaceted signaling pathways. The present study investigated the beneficial effects of CAR and ALA against HH-associated muscle loss. Methodology: Simulated HH exposure was performed in an animal decompression chamber. Gastric oral administration of CAR (50 mg·kg-1) and ALA (450 mg·kg-1) were given daily for 3 days and at the end of the treatment, hindlimb skeletal muscle tissue was excised for western blot and biochemical assays. Results: Cosupplementation of CAR and ALA alone was able to ameliorate the hypoxia-induced inflammation, oxidative stress (FOXO), ER stress (GRP-78), and atrophic signaling (MuRF-1) in the skeletal muscles. Creatinine phospho kinase activity and apoptosis were also decreased in CAR- and ALA-supplemented rats. However, CAR showed enhanced protection in HH-induced muscle loss as CAR supplementation was able to enhance protein concentration, body weight, and decreased the protein oxidation and ALA administration was not able to restore the same. Conclusions: Hence, the present comprehensive study supports the fact that CAR (50 mg·kg-1) is more beneficial as compared with ALA (450 mg·kg-1) in ameliorating the hypoxia-induced skeletal muscle loss.

Preoperative small airway dysfunction is associated with skeletal muscle loss in early-stage non-small cell lung cancer.

BACKGROUND: Postoperative skeletal muscle loss (SM loss) was reported to be associated with a poor prognosis in early-stage non-small cell lung cancer (NSCLC). Small airway dysfunction (SAD) is a common but neglected respiratory abnormality. Little information is known about the association between preoperative SAD and postoperative SM loss in early-stage NSCLC. Therefore, this study aimed to investigate the correlation between preoperative SAD and SM loss after surgery in early-stage NSCLC patients. METHODS: There were 348 NSCLC patients with stages I-IIIA in this study from January 2017 to December 2020. All CT images were contrast-enhanced scans, and the skeletal muscle index (SMI) was measured using CT images. A 10.0% decrease in SMI over 12 months was determined as the cut-off value to define excessive SM loss. Logistic regression analyses were used to examine the relationship between SAD and SM loss. RESULTS: This study included 348 subjects who underwent pulmonary operation (159 males and 189 females; mean age: 57.5 ± 8.8 years). 152 (43.7%) patients were identified as having SAD before surgery, and 179 patients (51.4%) were identified as having SM loss after 1 year. Moreover, a higher incidence of SAD was found in the SM loss group compared with that in the non-SM loss group (52.0% vs. 34.9%, p = 0.001). The patients with SAD were older, had larger tumor size, and had lower albumin levels. Furthermore, there were significant correlations between the lung function parameters manifesting SAD and the percentage change in SMI (for the forced expiratory flow when 75% of forced vital capacity has been exhaled (FEF75%), Pearson r=-0.107, p = 0.046; for FEF50%, r = -0.142, p = 0.008; and for FEF25-75%, r=-0.124, p = 0.021; respectively). However, no significant correlations were found between SMI and the lung function parameters reflecting proximal airway obstruction (p > 0.05). Logistic regression analysis revealed that preoperative SAD (HR, 2.465; 95% CI, 1.256-4.838; p = 0.009) was independent risk factor for postoperative SM loss in early-stage NSCLC. In addition, multivariable analysis revealed that SAD (HR, 1.816; 95% CI, 1.025-3.216, P = 0.041) were associated with postoperative complications. CONCLUSION: Preoperative SAD is significantly associated with postoperative complications and SM loss in early NSCLC patients. Our results suggest that preoperative assessment of SAD may be useful for risk stratification of surgical candidates with potential for targeted interventions.

Sarcopenia in chronic viral hepatitis: From concept to clinical relevance.

Although the frequency of metabolic risk factors for cirrhosis and hepatocellular carcinoma (HCC) is increasing, chronic hepatitis B (CHB) and chronic hepatitis C (CHC) remain the most relevant risk factors for advanced liver disease worldwide. In addition to liver damage, hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are associated with a myriad of extrahepatic manifestations including mixed cryoglobulinaemia, lymphoproliferative disorders, renal disease, insulin resistance, type 2 diabetes, sicca syndrome, rheumatoid arthritis-like polyarthritis, and autoantibody production. Recently, the list has grown to include sarcopenia. Loss of muscle mass or muscle function is a critical feature of malnutrition in cirrhotic patients and has been found in approximately 23.0%-60.0% of patients with advanced liver disease. Nonetheless, among published studies, there is significant heterogeneity in the aetiologies of hepatic diseases and measurement methods used to determine sarcopenia. In particular, the interaction between sarcopenia, CHB and CHC has not been completely clarified in a real-world setting. Sarcopenia can result from a complex and multifaceted virus-host-environment interplay in individuals chronically infected with HBV or HCV. Thus, in the present review, we provide an overview of the concept, prevalence, clinical relevance, and potential mechanisms of sarcopenia in patients with chronic viral hepatitis, with an emphasis on clinical outcomes, which have been associated with skeletal muscle loss in these patients. A comprehensive overview of sarcopenia in individuals chronically infected with HBV or HCV, independent of the stage of the liver disease, will reinforce the necessity of an integrated medical/nutritional/physical education approach in the daily clinical care of patients with CHB and CHC.

Physical exercise attenuates age-related muscle atrophy and exhibits anti-ageing effects via the adiponectin receptor 1 signalling.

BACKGROUND: Although the adiponectin signalling exerts exercise-mimicking effects, whether this pathway contributes to the anti-ageing benefits of physical exercise has not been established yet. METHODS: Swim exercise training and wheel running were used to measure lifespan in the nematode Caenorhabditis elegans and skeletal muscle quality in mice, respectively. Muscle weight, muscle fibre cross-sectional area (CSA) and myonuclei number were used to evaluate muscle mass. RNA sequencing (RNA-Seq) analysis of skeletal muscle in exercised mice was used to study the underlying mechanisms. Western blot and immunofluorescence were performed to explore autophagy- and senescence-related markers. RESULTS: The C. elegans adiponectin receptor PAQR-1/AdipoR1, but not PAQR-2/AdipoR2, was activated (3.55-fold and 3.48-fold increases in p-AMPK on Days 1 and 6, respectively, P < 0.001), which was involved in lifespan extension in exercised worms. Exercise training increased skeletal muscle mass index (1.29-fold, P < 0.01), muscle weight (1.75-fold, P < 0.001), myonuclei number (1.33-fold, P < 0.05), muscle fibre CSA (1.39-fold, P < 0.05) and capillary abundance (2.19-fold, P < 0.001 for capillary density; 1.58-fold, P < 0.01 for capillary number) in aged mice. Physical exercise reduced protein (2.94-fold, P < 0.001) and mRNA levels (1.70-fold, P < 0.001) of p16INK4a , a marker for cellular senescence, in skeletal muscle of aged mice. These beneficial effects of exercise on skeletal muscle of mice were dependent on AdipoR1. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis for differentially expressed genes in skeletal muscle between exercised mice with and without AdipoR1 knockdown by RNA-Seq analysis revealed that several KEGG pathways, such as 'AMPK signalling pathway' (P < 0.001), 'FOXO signalling pathway' (P < 0.001) and 'autophagy' (P < 0.001) were overrepresented. Knockdown of FoxO3a inhibited exercise-mediated beneficial effects on skeletal muscle quality of mice by inhibiting autophagy/mitophagy (3.81-fold reduction in LC3-II protein, P < 0.001; 1.53-fold reduction in BNIP3 protein, P < 0.05). Knockdown of daf-16, the FoxO homologue in C. elegans, reduced autophagy (2.77-fold and 2.06-fold reduction in GFP::LGG-1 puncta in seam cells and the intestine, respectively, P < 0.05) and blocked lifespan extension by exercise in worms. CONCLUSIONS: Our findings provide insights into how the AdipoR1 pathway has an impact on the anti-ageing benefits of exercise and implicate that activation of the AdipoR1 signalling may represent a potential therapeutic strategy for reducing age-related loss of skeletal muscle.

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 Loss During Neoadjuvant Chemotherapy Predicts the Incidence of Postoperative Infectious Complications in Esophageal Cancer Patients Undergoing Esophagectomy.

BACKGROUND/AIM: Malnutrition, immune deficiency, and skeletal muscle loss are associated with a risk of postoperative complications in patients with various types of cancer. This study evaluated whether malnutrition, immunological deficiencies, and skeletal muscle loss during neoadjuvant chemotherapy (NAC) predict postoperative complications in patients with esophageal cancer. PATIENTS AND METHODS: We retrospectively reviewed 123 patients with esophageal squamous cell carcinoma treated with NAC and esophagectomy at our hospital between 2014 and 2019. Patients were divided into two groups based on the presence or absence of postoperative infectious complications, such as pneumonia, anastomotic leakage, surgical site infections, pyothorax, acalculous cholecystitis, and peripheral phlebitis. Neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and Onodera prognostic nutritional index were used as indicators of systemic inflammation and nutritional status. Skeletal muscle mass was evaluated using the skeletal muscle index (SMI), calculated by evaluating the total cross-sectional area of muscle tissue at the third lumbar level in computed tomography imaging. Univariable and multivariable logistic regression analyses were used to identify predictors of postoperative infectious complications. RESULTS: Postoperative infectious complications occurred in 41 patients (33.3%). A reduction in SMI was observed in 105 patients (87.8%) during NAC. Univariable and multivariable analyses indicated that the reduction in SMI during NAC was an independent predictor of postoperative complications (odds ratio=0.89; 95% confidence interval=0.79-0.99; p=0.048). CONCLUSION: Skeletal muscle loss during NAC is a useful predictor of postoperative complications in patients with esophageal cancer undergoing esophagectomy.

Significance of Skeletal Muscle Loss in Liver Hypertrophy in Patients Undergoing Portal Vein Embolization Before Major Hepatectomy: Assessment With Body Composition and Nutritional Indicators.

BACKGROUND/AIM: The relationship between body composition including skeletal muscle and liver hypertrophy initiated by portal vein embolization (PVE) for major hepatectomy has not been clarified. This study aimed to investigate the effects of skeletal muscle, body adipose, and nutritional indicators on liver hypertrophy. PATIENTS AND METHODS: Fifty-nine patients who underwent PVE scheduled for major right-sided hepatectomy were included. The skeletal muscle area of L3 as skeletal muscle index was calculated. The relationship between skeletal muscle loss and clinical variables was assessed. We also evaluated the relationship between >30% liver growth or >12% liver growth/week after PVE. RESULTS: Skeletal muscle loss was observed in 39 patients (66.1%) and associated with zinc deficiency, visceral adipose index, liver growth rate, and liver growth rate/week. Multivariate analysis indicated that future liver volume and skeletal muscle index were associated with >30% liver growth, and functional future liver volume and skeletal muscle index were associated with >12% liver growth/week. CONCLUSION: Loss of skeletal muscle, and a small future remnant liver volume, attenuates liver hypertrophy initiated by PVE. Strength building and nutritional supplementation may have positive effects on liver hypertrophy after PVE.

Survival Impact of Postoperative Skeletal Muscle Loss in Gastric Cancer Patients Who Underwent Gastrectomy.

BACKGROUND/AIM: It has recently been recognized that preoperative sarcopenia contributes to postoperative complications and overall survival in gastric cancer (GC). However, few studies have investigated the relationship between postoperative skeletal muscle loss (SML) and survival in GC, despite the inevitability of body weight loss after gastrectomy in most GC patients. Herein, we studied the impact of postoperative SML on GC prognosis. PATIENTS AND METHODS: A total of 370 patients with GC who underwent curative gastrectomy were retrospectively evaluated in this study. Postoperative SML was assessed on computed tomography (CT) images taken before surgery and 1 year after surgery. The impact of postoperative SML on survival was evaluated. RESULTS: Postoperative severe SML was significantly associated with presence of comorbidities, higher tumor stage, higher postoperative complication rate and longer hospital stay. Univariate and multivariate analyses of prognostic factors for overall survival revealed that SML was an independent indicator of poor prognosis, along with age, tumor stage, preoperative sarcopenia, and operation time (hazard ratio, 2.65; 95% confidence interval, 1.68-4.20, p<0.0001). There was a strong association of severe postoperative SML with decreased overall survival in patients with preoperative sarcopenia. CONCLUSION: To improve the prognosis of GC patients after surgery, it is important to prevent postoperative SML as well as preoperative sarcopenia. Perioperative multimodal interventions including nutritional counseling, oral nutritional supplements, and exercise are required to prevent SML after gastrectomy.

Muscle loss 6 months after surgery predicts poor survival of patients with non-metastatic colorectal cancer.

Background: Muscle loss is a common characteristic of cancer-related malnutrition and a predictor of poorer prognosis in oncological patients. This study evaluated the association between altered body composition 6 months after surgery and the prognosis in patients with non-metastatic colorectal cancer. Materials and methods: A total of 314 patients who underwent elective curative surgery were enrolled in the study. The third lumbar CT images on preoperative and 6-months postoperative were collected to calculate the skeletal muscle index (SMI), visceral adiposity index (VATI), and subcutaneous adiposity index (SATI). Sarcopenia was defined by the cut-off values reported in the literature, and risk factors affecting overall survival (OS) and disease-free survival (DFS) in CRC were analyzed using Cox regression models. Results: Eighty-two of 314 patients (26.1%) with CRC were diagnosed with sarcopenia before surgery, the preoperative sarcopenia was not significantly associated with the prognosis of CRC patients. There were significant differences in frequency of complications between patient groups according to sarcopenia (41.5 vs. 21.4%, p = 0.004). The Postoperative LOS (11.21 ± 3.04 vs. 8.92 ± 2.84, p < 0.001) was longer in the sarcopenia group than in the non-sarcopenia group, and 30-d readmission (24.4 vs. 6.0%, p < 0.001) was higher in the sarcopenia group compared to the non-sarcopenia group. In multivariate analysis, 6-months SMI loss > 10% after surgery was independently associated with poorer OS [hazard ratio (HR) = 3.74; 95% confidence interval (CI) 1.96 to 7.12; P < 0.001] and DFS (HR = 3.33; 95% CI, 1.71 to 6.47; P < 0.001). SMI changes were moderately correlated with changes in body mass index (BMI) (R = 0.47, P < 0.001). Conclusion: 6-months muscle loss after surgery may affect overall and disease-free survival and was an independent predictor of prognosis in patients with CRC.

Endothelial Damage and Muscle Wasting in Cardiac Surgery Patients.

This is a post-hoc analysis to assess the effect of anesthesia, surgical trauma, and extracorporeal circuit on endothelial integrity, microvascular permeability, and extracellular fluid balance, as well as on skeletal muscle catabolism, in patients undergoing elective cardiac surgery. We included 127 well-nourished patients undergoing "on-pump" elective cardiac surgery. One day prior to surgery (D0) and again on postoperative day 7 (POD7), body mass index, body composition assessment, hand-grip strength (HGS), and mid-upper arm muscle circumference (MAMC) were measured. Patients were assigned to early recovery (ER) and late recovery (LR) groups, depending on the duration of ICU stay (cut-off 48 hours). The magnitude of change (Δ) in all parameters studied was assessed in ER versus LR groups, regarding (i) epithelial tissue dysfunction (Δ-Extra-Cellular Water percentage (Δ-ECW%), Δ-Phase Angle (Δ-PhA)), (ii) skeletal muscle mass catabolism (Δ-Skeletal muscle mass reduction%, Δ-Hand Grip Strength (Δ-HGS) and Δ-Mid Upper-Arm Muscle Circumference (Δ-MAMC)). Baseline measurements were similar in both groups. A significant difference was observed in all Δ-parameters studied (Δ-ECW%, Δ-PhA and muscle catabolism, Δ-HGS, Δ-MAMC), the worse results being correlated to the LR group. The results raise the issue that patients with early recovery may silently have pathological conditions, continuing even on the day of discharge - further research should be planned.