Skeletal Muscle Loss Research Articles

Prognostic Role of Low-Skeletal Muscle Mass on Staging Computed Tomography in Metastasized Colorectal Cancer: A Systematic Review and Meta-Analysis

BackgroundLow-skeletal muscle mass (LSMM) is defined as skeletal muscle loss, which can be assessed by imaging. Our aim was to establish the effect of LSMM on overall survival (OS) in metastasized colorectal cancer patients based on a large patient sample. Patients and MethodsMEDLINE library, EMBASE, and SCOPUS databases were screened for the associations between LSMM and mortality in metastasized colorectal cancer patients up to March 2022. The primary aim of the systematic review was to investigate the influence of LSMM on overall survival (OS) by means of the effect of measure hazard ratio. Fifteen studies were included into the present analysis. ResultsThe included studies comprised 1744 patients. The frequency of LSMM was 46.2%. Associations between LSMM and OS were as follows: hazard ratio (HR) = 1.34 (95% confidence interval [CI] 0.94-1.91), P = .10 in univariable analysis and HR = 2.05 (95% CI 1.18-3.56), P = .01 in multivariable analysis. LSMM influenced OS in patients undergoing first-line chemotherapy, HR = 1.51 (95% CI 1.20-1.89), P = .0004. In patients undergoing second- and third-line chemotherapy, LSMM was not associated with OS, HR = 1.43 (95% CI 0.65-3.14), P = .37 Also, LSMM did not affect OS in patients with resection of hepatic metastases, HR = 0.93 (95% CI 0.70-1.24), P = .63. LSMM tended to affect progression-free survival, HR = 1.49 (95% CI 0.94-2.35), P = .09. LSMM did not predict treatment toxicity, odds ratio (OR) = 1.52 (95% CI 0.84-2.72), P = .16. ConclusionLSMM occurs in 46.2% of patients with metastasized colorectal cancers. LSMM is associated with OS in patients undergoing first-line chemotherapy. LSMM does not affect OS in second- and third-line chemotherapy and in patients undergoing resection of hepatic metastases. LSMM is not associated with progression-free survival and treatment toxicity.

WITHDRAWN: Do skeletal muscle index and myosteatosis impact postoperative outcomes after liver transplantation?

• Skeletal muscle loss and myosteatosis is a frequent complication in patients with chronic or end-stage liver disease • The etiology of malnutrition in patients with chronic or end-stage liver disease is multifactorial. • Computed tomography (CT) with automated or semiautomated body composition analysis at the third lumbar vertebra has emerged as an objective method of defining the nutritional status of patients with chronic liver disease. • Nutritional status of a liver recipient is important, however due to complexity of liver transplant treatment not crucial. • Standardization and uniformity in definitions, methods, and cut-off points are crucial to producing reliable data in the future . Liver transplantation offers curative treatment to patients with acute liver failure and chronic end-stage liver disease. The impact of nutritional status on postoperative outcomes after liver transplantation remains poorly understood. The present study investigated the predictive value of skeletal muscle index (SMI) and myosteatosis (MI) on postoperative outcomes after liver transplantation. : Data of 138 adult patient patients who underwent their first orthotopic liver transplantation were retrospectively analysed. SMI and MI in CT scan at the third lumbar vertebra level were calculated, and groups with and without low muscle mass and myosteatosis were compared for the length of ICU and hospitalization, postoperative complications, infection, and graft rejection. : In 63% of male and 28.9% of female recipients, low SMI was found. High MI was found in 45(32.6%) patients. Male patients with high SMI had longer ICU stay ( P <0.025). Low SMI had no influence on ICU stay in female patients ( P =0.544) and length of hospitalisation (male, P >0.05; female, P =0,843). The presence of MI did not influence ICU stay ( P =0.161) or hospitalization ( P =0.771). Combining SMI and MI as predictive factors of poor outcome after liver transplantation had no influence on postoperative complication rates (males, P =0,883; females, P =0.113; both groups, P =0.839) and infection rate (males, P =0.293, females, P =0.285, both groups, P = 0.703). Graft rejection was not influenced by low SMI (males, P =0.875; females, P =0.135) and MI ( P =0.449). : In our study, changes in body composition of liver transplant recipients observed with SMI and MI had no impact on postoperative course after liver transplantation in patients with end-stage liver disease. Standardization and uniformly accepted definitions, methods, and cut-off points are crucial to producing reliable data in the future.

CT scan versus bioelectrical impedance spectrometry sarcopenia assessment to predict chemotherapy toxicity in early breast cancer.

12078 Background: There is growing literature on the impact of the progressive loss of skeletal muscle known as sarcopenia in women with early breast cancer (EBC). Imaging techniques such as Computed Tomography (CT) scans are the most studied methods to detect sarcopenia in patients with cancer; however, most patients with EBC do not require routine CT scans. Bioelectrical impedance spectrometry (BIS) is a method that does not expose patients to radiation and provides measurements to assess sarcopenia instantaneously. The extent to which BIS-assessed sarcopenia correlates with CT-assessed sarcopenia is uncertain. It is also unclear whether sarcopenia detected with either method can be associated with chemotherapy tolerance To address these questions, we evaluated the correlation between CT and BIS sarcopenia and associations of sarcopenia by each method with chemotherapy related outcomes in patients with EBC. Methods: This retrospective study identified patients with EBC who received chemotherapy (ACT, TC, TH, THP), underwent BIS analyses (ImpediMed) at any point between diagnosis and treatment completion and also received a CT abdomen including L3 level. Axial CT L3 segments were analyzed using Slice-O-Matic software. CT L3, and BIS generated the Skeletal Muscle (SM). Skeletal Muscle Index (SMI) was then calculated to assess for sarcopenia: BIS SMI= (SM in kg)/ (patient height, m2) and CT L3 SMI (SM cm2/ height m2). Patients were divided into normal SMI, and sarcopenia (if BIS was used SMI &lt;6.75 kg/m2 and if CT SMI &lt;40 cm2/m2). Patient medical records were reviewed for patient characteristics, grade 3 and 4 toxicity, including neuropathy symptoms, chemotherapy dose reductions, early treatment discontinuation or need for hospitalization during chemotherapy treatment. Spearman's rank coefficient was used to assess the correlation between CT SMI and BIS SMI. Multivariable logistic regression was used to associate sarcopenia with outcomes, controlling for age and BMI. Results: 361 patients received chemotherapy, underwent BIS; of those 171 had L3 CT scans. The correlation between L3 CT SMI and BIS SMI was r= 0.64 p&lt;0.0001. In the multivariable model, sarcopenia assessed by L3 CT scan was associated with chemotherapy dose reduction (CI 0.04-0.60 p=0.01) and neuropathy (CI 0.10-0.95 P=0.04) but not with grade 3 or 4 chemotherapy toxicity (CI 0.13-1.09 p=0.07), early treatment discontinuation (p=0.3) or hospitalization (p=0.60). Sarcopenia assessed by BIS was associated with grade 3 or 4 chemotherapy toxicity (CI 0.2-0.83 p=0.01), neuropathy (CI 0.1-0.51 p=0.0003), early treatment discontinuation (OR 0.26 CI 0.11-0.80 p=0.001), and hospitalization (CI 0.12-0.68 p=0.004). Conclusions: There is a strong correlation between L3 CT scan and BIS screened sarcopenia in patients with EBC. Sarcopenia detected with either CT L3 or BIS is associated with worse chemotherapy tolerance.

Evaluation of weight gain and overall survival of patients with advanced non–small cell lung cancer (NSCLC) treated with first-line platinum-based chemotherapy.

9088 Background: Cachexia is a multifactorial syndrome frequently associated with cancer characterized by anorexia and unintentional weight loss, including skeletal muscle loss, fatigue, functional impairment, poor quality of life, and worse survival. The objective of this post-hoc analysis was to examine the relationship between weight gain and overall survival (OS) in patients with NSCLC treated with first-line platinum-based regimens. Methods: Data were pooled from three phase 3 clinical trials (NCT00254891, NCT00254904, and NCT00596830) conducted between Nov 2005 and Mar 2011 in patients with advanced NSCLC (stage IIIB or stage IV) treated with first-line standard-of-care (SOC) chemotherapy (control arm). Weight was recorded at baseline, prior to dosing on day 1 of each 3-week treatment cycle (up to 6 cycles), and post-treatment according to each study’s schedule. Weight gain was categorized as &gt; 0%, &gt; 2.5%, and &gt; 5% increase from baseline up to 4.5 months. Cox Proportional Hazards modeling of OS including time to weight gain and time to confirmed objective response (RECIST v1.0) and baseline covariates were used to estimate hazard ratios (HR) for each category. Results: The total 1,030 patients from the SOC control arms were predominantly male (70.5%) with Stage IV NSCLC (88.5%) and a mean age (SD) of 60.9 (9.4) years and BMI 24.6 (4.4) kg/m2. Overall, 486 (47.2%), 299 (29.0%), and 164 (15.9%) patients experienced weight gain from baseline of &gt; 0%, &gt; 2.5%, and &gt; 5%, respectively. Median time to &gt; 0%, &gt; 2.5%, and &gt; 5% weight gain was 24, 43, and 64 days, respectively. After adjusting for statistically significant time-dependent confirmed objective response, the risk of death was significantly less for patients with weight gain. For patients with &gt; 0% vs. ≤0% weight gain, HR was 0.70 (95%CI 0.61, 0.82) with median OS of 13.6 vs. 8.3 months. For patients with &gt; 2.5% vs. ≤2.5% weight gain, HR was 0.70 (95%CI 0.59, 0.83) with median OS of 15.3 vs. 9.1 months. For patients with &gt; 5% vs. ≤5% weight gain, HR was 0.76 (95%CI 0.61, 0.94) with a median OS of 14.4 vs. 9.8 months. Conclusions: In this pooled analysis, weight gain during treatment with first-line platinum-based chemotherapy was associated with a significantly reduced risk of death in patients with advanced NSCLC, independent of tumor response defined by RECIST criteria. The survival benefit was comparable for &gt; 2.5% vs. &gt; 5% weight gain. Weight gain of 2.5% may be an earlier predictor of survival outcomes and may have implications for the design of cancer cachexia trials. Clinical trial information: NCT00254891, NCT00254904, and NCT00596830.

Extracellular polysaccharides purified (Polycan) from Aureobasidium pullulans SM‑2001 improves pathophysiology of dystrophin-deficient mdx mice

BackgroundDuchenne muscular dystrophy is a hereditary muscular disease involving degeneration (i.e. atrophy and loss of muscle fibres) of skeletal muscles, including the diaphragm, and progressively severe functional decline. A previous study shows Polycan, a type of β-glucan derived from the black yeast Aureobasidium pullulans (SM-2001), promotes osteogenicity and bone loss, and possesses anti-inflammatory activity to induce inflammatory cytokines in human immune and cancer cells.ObjectiveIn this study, we evaluated changes in exercise load behaviour measurements and changes in muscle-related physiological indicators following oral administration of Polycan in mdx mice, an experimental animal model of Duchenne muscular dystrophy.ResultIn mdx mice, Polycan prevented weight loss and thickness of skeletal muscle. In addition, by monitoring increases in running time of mice on treadmills and performing a grip strength test, we confirmed reduced muscle function was recovered to some extent after administering Polycan to mdx mice. In addition, we confirmed that Polycan significantly altered mRNA expression in a concentration-dependent manner, whereby myogenic transcription factors (MyoD, Myf5 and Myogenin) increased and FoxO3α, MuRF1 and Atrogin-1 decreased. We aimed to investigate the mechanism of action in Polycan on energy metabolism of p-AMPK, SIRT1 and PGC1α with apoptosis expression levels as factors related to signalling pathways. Expression ratios of cleaved-caspase-3/caspase-3 and Bax/Bcl-2 in the Polycan extract-administered group increased compared with the control group.ConclusionThese results demonstrate that Polycan can improve and protect muscle atrophy by preventing apoptosis via pathway regulation related to myogenic transcription factors and energy metabolism in mdx mice.

Frataxin deficiency lowers lean mass and triggers the integrated stress response in skeletal muscle.

Friedreich’s ataxia (FRDA) is an inherited disorder caused by reduced levels of frataxin (FXN), which is required for iron-sulfur cluster biogenesis. Neurological and cardiac comorbidities are prominent and have been a major focus of study. Skeletal muscle has received less attention despite indications that FXN loss affects it. Here, we show that lean mass is lower, whereas body mass index is unaltered, in separate cohorts of adults and children with FRDA. In adults, lower lean mass correlated with disease severity. To further investigate FXN loss in skeletal muscle, we used a transgenic mouse model of whole-body inducible and progressive FXN depletion. There was little impact of FXN loss when FXN was approximately 20% of control levels. When residual FXN was approximately 5% of control levels, muscle mass was lower along with absolute grip strength. When we examined mechanisms that can affect muscle mass, only global protein translation was lower, accompanied by integrated stress response (ISR) activation. Also in mice, aerobic exercise training, initiated prior to the muscle mass difference, improved running capacity, yet, muscle mass and the ISR remained as in untrained mice. Thus, FXN loss can lead to lower lean mass, with ISR activation, both of which are insensitive to exercise training.

Association Between Body Composition and Development of Glucose Intolerance after Allogeneic Hematopoietic Cell Transplantation.

Allogeneic hematopoietic cell transplantation (HCT) recipients have increased risk of developing glucose intolerance and diabetes mellitus (DM). The strongest risk factor for glucose intolerance is being overweight/obese, as determined by body mass index (BMI), which does not account for differences in body composition. We examined the association between body composition measures from pre-HCT CT and early-onset (≤30 days) de novo glucose intolerance after HCT, and determined its impact on nonrelapse mortality (NRM). This study included 749 patients without pre-HCT DM. Skeletal muscle loss [abnormal skeletal muscle gauge (SMG)] and abnormal visceral adiposity (VA) were defined by sex-specific tertiles. Fine-Gray proportional subdistribution HR estimates and 95% confidence intervals (CI) were obtained to determine the association between muscle loss and VA and development of glucose intolerance. 1 year NRM was calculated for patients alive at day 30. Median age at HCT was 50.2 years. By day 30, 8.1% of patients developed glucose intolerance and 731 remained alive. In multivariable analysis, abnormal SMG was associated with increased risk of glucose intolerance in nonoverweight (BMI &lt; 25 kg/m2) patients (HR = 3.00; 95% CI, 1.15-7.81; P = 0.024); abnormal VA was associated with increased risk of glucose intolerance in overweight/obese patients (HR = 2.26; 95% CI, 1.24-4.12; P = 0.008). Glucose intolerance was independently associated with NRM (HR = 1.88; 95% CI, 1.05-3.39; P = 0.035). Abnormal SMG and VA were associated with glucose intolerance in nonoverweight and overweight/obese patients, respectively, which contributed to increased risk of 1 year NRM. This information may guide personalized interventions to decrease the risk of adverse outcomes after HCT. See related commentary by Giri and Williams, p. 2002.

Neurological restorative effects of the flavanol (‐)‐epicatechin in a rodent model of Gulf War Illness

Gulf War Illness (GWI) afflicts ~30% of the US military personnel who served in the 1990‐91 Persian Gulf War. Symptoms include cognitive deficits, muscle pain, weakness, exercise intolerance and fatigue which are still present after 30 years in war Veterans. Suspect causal agents include exposure to the compounds pyridostigmine (PB), permetrim (PM) and N,N‐diethyl‐m‐toluamide (DEET) which were used as protectants against nerve gases (PB) and insects. We previously reported a study to model GWI in which young male rats were provided PB, PM and DEET at equivalent human doses and physical restraint (to induce stress) for 3 weeks. In GWI animals, skeletal muscle weight was 35% lower vs. controls, which correlated with decreases in myofiber area, limb strength and treadmill time/distance. In a follow up study, we reported on the beneficial effects of the cacao flavanol (‐)‐epicatechin (epi) provided for 2 weeks by oral gavage on skeletal muscle atrophy and loss of function. In the current study, we wished to explore the potential of Epi to beneficially impact neurological measures of memory including multiple markers of hippocampus structure and function. Male Wistar rats underwent 3 weeks of exposure to either vehicles or DEET, PM, PB and stress. Subgroups of GWI rats (n=7/subgroup) received 15 days of either water (vehicle) or 1 mg/kg/day of Epi treatment by oral gavage and were compared to normal control (n=7). Object recognition tasks were performed to assess effects on memory and hippocampus samples were collected for histological and biochemical analysis. Results demonstrate that Epi treatment yields significant improvements in short and long‐term memory vs. GWI rats yielding values similar to those of controls. The assessment of hippocampus oxidative stress (protein carbonylation) and pro‐inflammatory cytokines levels (ELISA) of IL‐1β, TNF‐α and IFN‐γ (figure) yielded significant increases with GWI that were fully normalized with Epi to become comparable to controls. Significant increases in markers of hippocampus neuroinflammation (Iba1 and GFAP) and cell death (caspase activity) were noted with GWI and were significantly reduced with Epi. The neuronal survival signaling pathways (TREM2, PI3K and AKT) were adversely impacted by GWI and were partially or fully restored by Epi. Multiple markers of mitochondrial function (citrate synthase activity and ATP levels) adversely impacted by GWI and were fully restored by Epi. Thus, in an animal model of GWI, Epi beneficially impacted markers of hippocampus neuroinflammation, oxidative stress, cell survival, neurotoxicity and mitochondrial function. Such effects translated into improvements in functional endpoints associated with memory centers. As per the recognized safety profile of Epi clinical studies are warranted to explore the effects of treatment in Gulf War Veterans.

The Role of Skeletal Muscle Intrinsic Clock in the Development and Progression of Cancer Cachexia

Cancer cachexia is a chronic wasting disorder characterized by severe loss of skeletal muscle that affects approximately 80% of cancer patients, accounting for about 20 – 30% of cancer‐related deaths. Altered rest‐activity is a hallmark of circadian disruption and is often seen in cachectic patients. Additionally, loss of skeletal muscle‐specific clock gene results in muscle atrophy similar to that seen in cancer cachexia. However, it is unknown how skeletal muscle clock gene expression is altered with the progression of cachexia. Therefore, we investigated skeletal muscle clock gene expression during cachexia. ApcMin/+mice (MIN) were harvested in the morning and evening and were analyzed for clock gene expression. There was no effect of cancer on muscle Bmal1 (p = 0.55) and Clock (p = 0.59) expression. Cry1 expression showed no significant difference compared to BL – 6 mice (p = 0.24). Per 2 (p = 0.07) and Per 3 (p = 0.02) increased expression in the evening; however there was no difference between MIN and BL – 6 (Per 2 p=0.97, Per 3 p=0.87). Rev‐ERBα showed decreased expression in BL – 6 mice in the evening (p&lt;0.001). However, there was no difference between the morning and evening MIN mice (p=0.31). RORα showed increased expression in BL – 6 mice in the evening (p = 0.03). Additionally, BL – 6 evening was significantly higher compared to MIN evening (p=0.01). However, there was no difference between the morning and evening MIN RORα expression (p&gt;0.99). In LLC conditioned media treated myotubes, myotube diameter was decreased (p&lt;0.001), and Bmal1 expression was decreased after 4 days in LLC conditioned media. In conclusion, the data suggest circadian clock expression is altered in a cachectic environment. Addition research is needed to understand the influence of these changes on the progression of cancer cachexia. Understanding the role of muscle‐specific circadian clock could lead to potential therapeutic interventions to attenuate cancer cachexia.

Restorative effects of epicatechin on ovariectomy induced loss of skeletal muscle structure‐function: Underlying mechanisms

Early menopause occurs in women under age 45 and is seen in ~5% of women. Women who experience estrogen deficiency at an early age (before menopause) are known to be at increased overall risk for premature morbidity and mortality. Also, higher rates of physical limitation are known to occur in surgically menopausal vs. naturally menopausal women. To the extent that muscle mass and strength decreases, it can foster lesser levels of overall physical activity which, can promote a further deterioration of the musculoskeletal system including bone density. We previously documented the capacity of the cacao flavanol (‐)‐epicatechin (Epi) to restore skeletal muscle (SkM) mass and strength in various models of disease. Our research group implemented a female Wistar rat model whereby ovariectomy (OVX) was used to assess its impact on SkM structure/function as well as on modulators of muscle mass (atrophy). Using this model, we tested the hypothesis that Epi can restore SkM structure and function and recognized modulators of muscle mass. For these experiments, female rats at the age of 6 months (n=9‐10/subgroups) were subjected to OVX and allowed to evolve for a period of 12 weeks. A subgroup was treated with Epi at the dose of 1 mg/kg/day (by gavage in water) 8 weeks after OVX. Intact animals subjected to a sham OVX and vehicle (water) were used as controls. Front limb strength (in Newtons =N) was assessed weekly resulting in a significant progressive drop in force with OVX that was fully restored with 4 weeks of Epi treatment (figure 1 top graphs). Overall exercise capacity was assessed by treadmill (bottom panels) demonstrating a decrease with OVX and an improvement in total treadmill time (in minutes) with Epi that was greater vs. controls. At the time of sacrifice, muscle weight of gastrocnemius was recorded and values normalized to tibial length demonstrating the development of significant atrophy with OVX and the restoring effects of Epi treatment. An assessment of factors recognized to induce a loss of muscle mass was pursued. Myostatin levels were measured in blood by ELISA while the relative protein levels for the recognized inducers of muscle atrophy Murf‐1 and atrogin‐1 by Western blots of gastrocnemius lysates. Relative changes were normalized for loading differences using GAPDH. Blood levels of the muscle atrophy inducer factor myostatin were significantly increased with OVX and were fully normalized by Epi. OVX led to the significant upregulation of Murf‐1 and atrogin‐1 and the normalization of such effects with Epi. OXV led to significant increases in pro‐inflammatory cytokines TNF‐α, IL‐1β, IL‐2 and IFN‐γ andf plasma oxidative stress leveles (protein carbonylation) that were completely normalized with Epi. Altogether, results demonstrate that OVX can significantly compromise SkM structure and function which can be fully reversed by the use of Epi. These effects are likely the results of the effects on recognized modulators of inflammation, oxidative stress and atrophy. Clinical trials are warranted as per the recognized safety profile of Epi in humans.

Duchenne muscular dystrophy trajectory in R-DMDdel52 preclinical rat model identifies COMP as biomarker of fibrosis

Duchenne muscular dystrophy (DMD) is a fatal muscle-wasting disorder caused by mutations in the Dystrophin gene and for which there is currently no cure. To bridge the gap between preclinical and therapeutic evaluation studies, we have generated a rat model for DMD that carries an exon 52 deletion (R-DMDdel52) causing a complete lack of dystrophin protein. Here we show that R-DMDdel52 animals recapitulated human DMD pathophysiological trajectory more faithfully than the mdx mouse model. We report that R-DMDdel52 rats displayed progressive and severe skeletal muscle loss associated with fibrotic deposition, fat infiltration and fibre type switch. Early fibrosis was also apparent in the cardiac muscle. These histological modifications led to severe muscle, respiratory and cardiac functional impairments leading to premature death around 1 year. Moreover, DMD muscle exhibited systemic inflammation with a mixed M1/M2 phenotype. A comparative single cell RNAseq analysis of the diaphragm muscle was performed, revealing cellular populations alteration and molecular modifications in all muscle cell types. We show that DMD fibroadipogenic progenitors produced elevated levels of cartilage oligomeric matrix protein, a glycoprotein responsible for modulating homeostasis of extracellular matrix, and whose increased concentration correlated with muscle fibrosis both in R-DMDdel52 rats and human patients. Fibrosis is a component of tissue remodelling impacting the whole musculature of DMD patients, at the tissue level but most importantly at the functional level. We therefore propose that this specific biomarker can optimize the prognostic monitoring of functional improvement of patients included in clinical trials.

Early volume loss of skeletal muscle after esophagectomy: a risk for late-onset postoperative pneumonia.

Late-onset postoperative pneumonia (LOPP) after esophagectomy is poorly understood. This study was designed to clarify the features and risk factors for this event. Patients who underwent esophagectomy for esophageal cancer between 2006 and 2016 were included. LOPP was defined as radiologically proven pneumonia that occurred over 3months after surgery, and clinically relevant late-onset postoperative pneumonia (CR-LOPP) was defined as LOPP that required administration of oxygen and antibiotics in the hospital and/or more intensive treatment. The total psoas muscle area (TPA) was measured using preoperative and postoperative (at 3months after surgery) computed tomography scan images. Potential risk factors for CR-LOPP were investigated. Among 175 study patients, 46 (26.3%) had LOPP, 29 (16.6%) of whom exhibited CR-LOPP with a cumulative incidence of 15.6% at 3years and 22.4% at 5years. Four (13.8%) of these patients died of LOPP. Univariable analysis showed that clinical stage ≥III (P = 0.005), preoperative prognostic nutritional index (PNI) <45 (P = 0.035), arrhythmia (P = 0.014), postoperative hospital stay ≥40days (P = 0.003), and percent decrease of TPA more than 5% (P < 0.001) were associated with CR-LOPP but not early onset postoperative pneumonia. Multivariable analysis revealed that clinical stage ≥III (hazard ratio [HR] 3.01, P = 0.004), postoperative hospital stay ≥40days (HR 2.51, P = 0.015), and percent decrease of TPA >5% (HR 9.93, P < 0.001) were independent risk factors for CR-LOPP. CR-LOPP occurred in over 20% of patients at 5years, and early postoperative loss of TPA was a potential trigger for this delayed complication.

Significance of Skeletal Muscle Loss in Resected Lung Cancer Patients Treated with Neoadjuvant Chemoradiotherapy

Significance of Skeletal Muscle Loss in Resected Lung Cancer Patients Treated with Neoadjuvant Chemoradiotherapy

Ninjin'yoeito, a traditional Japanese medicine, attenuates age-related deficits of muscle performance, self-care motivation, and body temperature in C57BL/6 mice.

As both physiological and psychological factors influence age-associated declines in older people, the development of drug therapy with multifaceted effects is required. To investigate the utility of ninjin'yoeito (NYT) against geriatric syndromes, we evaluated the effects of NYT on age-related declines in old C57BL/6 mice (88-week-old) as a preclinical model of frailty progression. Here, we showed that NYT reversed the decline of rectal temperature in old mice and also improved forelimb grip strength compared with that in the old control group without affecting skeletal muscle loss. Moreover, NYT significantly increased the duration of grooming after a sucrose solution was sprayed, which reflected self-care motivation. Finally, we revealed the antioxidant effects of NYT using a cell-free assay. These results suggest that NYT can improve both physiological and psychological declines associated with aging, and the mechanism may include antioxidant effects. NYT may have potential utility for maintaining the health of older people.

Quantitative estimation of muscle mass in older adults at risk of sarcopenia using ultrasound: a cross-sectional study.

Sarcopenia is an age-associated syndrome of decreased skeletal muscle function and loss of muscle mass. This cross-sectional study was designed to investigate whether ultrasound can be used to quantitatively estimate muscle mass in older adults as an efficient assistive method for the diagnosis of sarcopenia. A cohort of 103 older adults older aged over 60 years who were at risk of sarcopenia, including 57 males and 46 females, was recruited. The participants underwent ultrasound to measure the muscle thickness (MT) of 11 sites across the whole body. Bioelectrical impedance analysis (BIA) was then used to estimate the appendicular muscle mass, and the correlation between skeletal muscle mass index (SMI) and MT at different sites was studied. Finally, muscle mass estimation algorithms for older adults were developed using multiple linear regression. Male participants had a significantly higher SMI (7.03±0.73 vs. 5.84±0.72 kg/m2, P<0.001) and higher MT than female participants at all 11 sites (all P<0.05). The MT of Site 7 (rectus femoris and intermedius femoris) in males had the strongest correlation with SMI (R=0.719, P<0.001). In females, the MT at Site 3 (flexor pollicis longus, flexor digitorum superficialis, and brachioradialis) had the strongest correlation with SMI (R=0.733, P<0.001). The MT of Site 7 was selected for a one-site algorithm; the R2 and standard error of estimate (SEE) values were 0.701 and 0.519 kg/m2, respectively. The MT of Site 3, Site 7, Site 1 (biceps and brachialis), and Site 9 (tibialis anterior) were selected for a four-site algorithm; the R2 and SEE values were 0.819 and 0.404 kg/m2, respectively. MT measured using ultrasound is correlated with SMI at some sites, and the correlations differ between men and women. When sex and age were included in the algorithm, the MT at Site 1, Site 3, Site 7, and Site 9 were valuable for estimating SMI, with Site 7 being the best parameter among them. Ultrasound-derived algorithms can achieve a satisfying fitting effect and provide new solutions for muscle mass estimation in older adults.

Baroreflex sensitivity in facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD), a common form of muscular dystrophy, is caused by a genetic mutation that alters DUX4 gene expression. This mutation contributes to significant skeletal muscle loss. Although it is suggested that cardiac muscle may be spared, people with FSHD have demonstrated autonomic dysregulation. It is unknown if baroreflex function, an important regulator of blood pressure (BP), is impaired in people with FSHD. We examined if baroreflex sensitivity (BRS) is blunted in patients with FSHD. Thirty minutes of resting BP, heart rate, and cardiovagal BRS were measured in 13 patients with FSHD (age: 50 ± 13 years, avg ± SD) and 17 sex‐ and age‐matched controls (age: 47 ± 14 years, p > 0.05). People with FSHD were less active (Activity Metabolic Index, AMI) (FSHD: 24 ± 30; controls: 222 ± 175 kcal/day; p < 0.001) but had a similar body mass index compared with controls (FSHD: 27 ± 4; controls: 27 ± 4 kg/m2; p > 0.05). BRSup (hypertensive response), BRSdown (hypotensive response), and total BRS were similar between groups (BRSup: FSHD: 12 ± 8; controls: 12 ± 5 ms/mmHg; BRSdown: FSHD: 10 ± 4; controls: 13 ± 6 ms/mmHg; BRS: FSHD: 14 ± 9; controls: 13 ± 6 ms/mmHg; p > 0.05). Mean arterial pressure was similar between groups (FSHD: 96 ± 7; controls: 91 ± 6mmHg). Individuals with FSHD had an elevated heart rate compared with controls (FSHD: 65 ± 8; controls: 59 ± 8 BPM; p = 0.03), but when co‐varied for AMI, this relationship disappeared (p = 0.39). These findings suggest that BRS is not attenuated in people with FSHD, but an elevated heart rate may be due to low physical activity levels, a potential consequence of limited mobility.

Skeletal muscle loss during neoadjuvant chemotherapy predicts poor prognosis in patients with breast cancer

BackgroundThe skeletal muscle index (SMI), which is calculated as the ratio of skeletal muscle area at the third lumbar vertebral level divided by height squared, has been considered a prognostic factor in patients with breast cancer. However, the prognostic impact of changes in SMI during treatment remains unclear. This study aimed to evaluate the influence of SMI changes in patients with breast cancer undergoing neoadjuvant chemotherapy (NAC).MethodsWe reviewed patients with breast cancer who underwent NAC and subsequent surgery for breast cancer between 2010 and 2017. The rate of SMI change during NAC was calculated, and the association between SMI changes and prognosis was retrospectively analyzed.ResultsIn total, 141 patients were evaluated. 48 (34.0%), 53 (37.6%), and 40 (28.4%) patients exhibited increased (≥ 3%), maintained (− 3% <, < 3%), and decreased (− 3% ≥) SMI during NAC, respectively. The decreased SMI group showed significantly poorer disease-free survival than the maintained and increased SMI groups (hazard ratio [HR] 8.29, p < 0.001 for the decreased vs. increased SMI groups; HR 3.49, p < 0.001 for the decreased vs. maintained SMI groups). Moreover, decreased SMI was an independent risk factor for disease-free survival in multivariate analysis (HR 3.68, p < 0.01).ConclusionsSkeletal muscle loss during NAC predicts poor prognosis. Our results underscore the importance of monitoring and maintaining skeletal muscle mass during NAC.

Non-linear Associations Between Visceral Adipose Tissue Distribution and Anthropometry-Based Estimates of Visceral Adiposity.

BackgroundRecent evidence suggests that excess visceral adipose tissue (VAT) is associated with future loss of subcutaneous adipose tissue (SAT) and skeletal muscle (SM) with aging. In clinical settings (abdominal) circumferences are commonly used to estimate body composition (BC). We aimed to study the linearity of VAT distribution ratios (i.e., VAT/SAT ratio and VAT/SM ratio), waist-to-hip ratio (WHR) and waist circumference (WC) with age and the relationship of VAT distribution ratios with anthropometry (i.e., WHR and WC).Materials and MethodsBC was determined using whole body magnetic resonance imaging in a large multi-ethnic group of 419 adults (42% white, 30% black, 15% Hispanic, 13% Asian, 1% other) with a BMI ranging from 15.9 to 40.8kg/m2. Linear and non-linear regression analysis was used to examine the linearity of VAT distribution ratios and anthropometry from 18 to 88 years. The relation between VAT distribution ratios and anthropometry was assessed separately.ResultsIn both sexes non-linear relationships were found between BC estimates and age, and between BC measures mutually. The ratios of VAT/SAT and VAT/SM showed quadratic relationships with age. VAT distribution ratios showed exponential or quadratic relationships with anthropometry with coefficients of determination ranging between 18 and 55%.ConclusionIn both sexes, VAT distribution ratios showed curvilinear relationships with age and with anthropometry. Given the sex differences in VAT distribution ratios, WHR and WC represent different BC proportions in men and women. These results emphasize the challenge when interpreting changes in BC based upon linear extrapolations in clinical practice.

IL-17A contributes to skeletal muscle atrophy in lung cancer-induced cachexia via JAK2/STAT3 pathway.

Cachexia is a complex metabolic syndrome that occurs in approximately 50% of patients with cancer. Skeletal muscle atrophy is the primary clinical feature. Interleukin (IL)-17A, a proinflammatory factor, plays an important role in many chronic inflammatory diseases. Here, we describe a novel signaling pathway through which IL-17A induced muscle atrophy. We conducted a retrospective clinical study to investigate the relationship between IL-17A and the skeletal muscle index in patients with lung adenocarcinoma. We also investigated the involvement of JAK2/STAT3 signaling pathway regarding the main features of cachexia by injecting Lewis lung carcinoma (LLC) cells into C57BL/6 mice as a model to replicate cancer-induced cachexia. In vitro, C2C12 myotubes were treated with recombinant IL-17A, anti-IL-17A monoclonal antibody, STAT3 inhibitor AG490, and LLC-conditioned medium. Cell viability and aging were also evaluated. We found that in cancer conditions, increased serum levels of IL-17A were related to muscle wasting. JAK2/STAT3 phosphorylation was observed in the muscle of LLC tumor-bearing mice, accompanied by decreased MHC/Myog levels and increased MuRF1/Atrogin-1 levels. Administration of anti-IL-17A monoclonal antibody and AG490 slowed muscle atrophy development. Consistent with the in vivo findings, C2C12 myotubes treated with IL-17A and LLC-conditioned medium demonstrated phosphorylated JAK2/STAT3 signaling, resulting in MHC loss and myotube atrophy. IL-17A also inhibited C2C12 cell proliferation, cell cycle breaking, and cellular senescence. Our results identify that phosphorylation of IL-17A/JAK2/STAT3 signaling pathway appears to be an important component in the pathogenesis of LLC tumor-induced cachexia. Targeted therapy of IL-17A may be a promising approach to reduce skeletal muscle loss in patients with cancer.

Preclinical Development of Bioengineered Allografts Derived from Decellularized Human Diaphragm.

Volumetric muscle loss (VML) is the traumatic/surgical loss of skeletal muscle, causing aesthetic damage and functional impairment. Suboptimal current surgical treatments are driving research towards the development of optimised regenerative therapies. The grafting of bioengineered scaffolds derived from decellularized skeletal muscle may be a valid option to promote structural and functional healing. In this work, a cellular human diaphragm was considered as a scaffold material for VML treatment. Decellularization occurred through four detergent-enzymatic protocols involving (1) sodium dodecyl sulfate (SDS), (2) SDS + TergitolTM, (3) sodium deoxycholate, and (4) TergitolTM. After decellularization, cells, DNA (≤50 ng/mg of tissue), and muscle fibres were efficiently removed, with the preservation of collagen/elastin and 60%–70% of the glycosaminoglycan component. The detergent-enzymatic treatments did not affect the expression of specific extracellular matrix markers (Collagen I and IV, Laminin), while causing the loss of HLA-DR expression to produce non-immunogenic grafts. Adipose-derived stem cells grown by indirect co-culture with decellularized samples maintained 80%–90% viability, demonstrating the biosafety of the scaffolds. Overall, the tested protocols were quite equivalent, with the patches treated by SDS + TergitolTM showing better collagen preservation. After subcutaneous implant in Balb/c mice, these acellular diaphragmatic grafts did not elicit a severe immune reaction, integrating with the host tissue.