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BACKGROUND: Low physical performance is associated with higher mortality rate in multiple pathological conditions. Here, we aimed to determine whether body composition and physical performance could be prognostic factors in non-small cell lung cancer (NSCLC) patients. Moreover, we performed an exploratory approach to determine whether plasma samples from NSCLC patients could directly affect metabolic and structural phenotypes in primary muscle cells. METHODS: This prospective cohort study included 55 metastatic NSCLC patients and seven age-matched control subjects. Assessments included physical performance, body composition, quality of life and overall survival rate. Plasma samples from a sub cohort of 18 patients were collected for exploratory studies in cell culture and metabolomic analysis. RESULTS: We observed a higher survival rate in NSCLC patients with high performance in the timed up-and-go (+320%; p = .007), sit-to-stand (+256%; p = .01) and six-minute walking (+323%; p = .002) tests when compared to NSCLC patients with low physical performance. There was no significant association for similar analysis with body composition measurements (p > .05). Primary human myotubes incubated with plasma from NSCLC patients with low physical performance had impaired oxygen consumption rate (-54.2%; p < .0001) and cell proliferation (-44.9%; p = .007). An unbiased metabolomic analysis revealed a list of specific metabolites differentially expressed in the plasma of NSCLC patients with low physical performance. CONCLUSION: These novel findings indicate that physical performance is a prognostic factor for overall survival in NSCLC patients and provide novel insights into circulating factors that could impair skeletal muscle metabolism.
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Despite advancements in treatment, approximately 25% of breast cancer patients experience long-term skeletal muscle wasting (SMW), which limits mobility, reduces drug tolerance and adversely impacts survival. By understanding the underlying molecular mechanisms of SMW, we may develop new strategies to alleviate this condition and improve the lives of breast cancer patients. Chemokines are small soluble factors that regulate homing of immune cells to tissues during inflammation. In breast cancers, overexpression of the C-C chemokine ligand 2 (CCL2) correlates with unfavorable prognosis. Elevated levels of CCL2 in peripheral blood indicate possible systemic effects of this chemokine in breast cancer patients. Here, we investigated the role of CCL2 signaling on SMW in a tumor and non-tumor context. In vitro, increasing concentrations of CCL2 inhibits myoblast and myotube function through C-C chemokine receptor 2 (CCR2) dependent mechanisms involving JNK, SMAD3 and AMPK signaling. In healthy mice, delivery of recombinant CCL2 protein promotes SMW in a dose dependent manner. In vivo knockdown of breast tumor derived CCL2 partially protects against SMW. Overall, chronic, upregulated CCL2/CCR2 signaling positively regulates SMW, with implications on therapeutic targeting.
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Gracilaria chorda (GC) is a red algal species that is primarily consumed in Asia. Here, we investigated the effect of GC on obesity-related skeletal muscle wasting. Furthermore, elucidating its impact on the activation of sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) constituted a critical aspect in understanding the underlying mechanism of action. In this study, 6-week-old male C57BL/6 mice were fed a high-fat diet (HFD) for 8 weeks to induce obesity, then continued on the HFD for another 8 weeks while orally administered GC. GC decreased ectopic fat accumulation in skeletal muscle and increased muscle weight, size, and function in obese mice. Furthermore, GC reduced skeletal muscle atrophy and increased hypertrophy in mice. We hypothesized that the activation of SIRT1/PGC1α by GC regulates skeletal muscle atrophy and hypertrophy. We observed that GC increased the expression of SIRT1 and PGC1α in skeletal muscle of mice and in C2C12 cells, which increased mitochondrial function and biogenesis. In addition, when C2C12 cells were treated with the SIRT1-specific inhibitor EX-527, no changes were observed in the protein levels of SIRT1 and PGC1α in the GC-treated C2C12 cells. Therefore, GC attenuated obesity-related muscle wasting by improving mitochondrial function and biogenesis through the activation of SIRT1/PGC1α in the skeletal muscle of mice.
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Rationale: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. Our previous studies have identified that nocturnal hypoxemia causes skeletal muscle loss (i.e., sarcopenia) in in vitro models of COPD. Objectives: We aimed to extend our preclinical mechanistic findings by analyzing a large sleep registry to determine whether nocturnal hypoxemia is associated with sarcopenia in patients with COPD. Methods: Sleep studies from patients with COPD (n = 479) and control subjects without COPD (n = 275) were analyzed. Patients with obstructive sleep apnea, as defined by apnea-hypopnea index ⩾ 5, were excluded. Pectoralis muscle cross-sectional area (PMcsa) was quantified using computed tomography scans performed within 1 year of the sleep study. We defined sarcopenia as less than the lowest 20% residuals for PMcsa of control subjects, which was adjusted for age and body mass index (BMI) and stratified by sex. Youden's optimal cut-point criteria were used to predict sarcopenia based on mean oxygen saturation during sleep. Additional measures of nocturnal hypoxemia were analyzed. The pectoralis muscle index (PMI) was defined as PMcsa normalized to BMI. Results: On average, males with COPD had a 16.6% lower PMI than control males (1.41 ± 0.44 vs. 1.69 ± 0.56 cm2/BMI; P < 0.001), whereas females with COPD had a 9.4% lower PMI than control females (0.96 ± 0.27 vs. 1.06 ± 0.33 cm2/BMI; P < 0.001). Males with COPD with nocturnal hypoxemia had a 9.5% decrease in PMI versus COPD with normal O2 (1.33 ± 0.39 vs. 1.47 ± 0.46 cm2/BMI; P < 0.05) and a 23.6% decrease compared with control subjects (1.33 ± 0.39 vs. 1.74 ± 0.56 cm2/BMI; P < 0.001). Females with COPD with nocturnal hypoxemia had an 11.2% decrease versus COPD with normal O2 (0.87 ± 0.26 vs. 0.98 ± 0.28 cm2/BMI; P < 0.05) and a 17.9% decrease compared with control subjects (0.87 ± 0.26 vs. 1.06 ± 0.33 cm2/BMI; P < 0.001). These findings were largely replicated using multiple measures of nocturnal hypoxemia. Conclusions: We defined sarcopenia in the pectoralis muscle using residuals that take into account age, BMI, and sex. We found that patients with COPD have a lower PMI than patients without COPD and that nocturnal hypoxemia was associated with an additional decrease in the PMI of patients with COPD. Additional prospective analyses are needed to determine a protective threshold of oxygen saturation to prevent or reverse sarcopenia due to nocturnal hypoxemia in COPD.
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Hipóxia , Doença Pulmonar Obstrutiva Crônica , Sarcopenia , Tomografia Computadorizada por Raios X , Humanos , Sarcopenia/complicações , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Masculino , Feminino , Hipóxia/etiologia , Hipóxia/complicações , Idoso , Pessoa de Meia-Idade , Polissonografia , Músculos Peitorais/diagnóstico por imagem , Estudos de Casos e Controles , Índice de Massa Corporal , Sistema de RegistrosRESUMO
Muscle wasting (sarcopenia) is one of the hallmarks of critical illness. Patients admitted to intensive care unit develop sarcopenia through increased protein catabolism, a decrease in protein syntheses, or both. Among the factors known to promote wasting are chronic inflammation and cytokine imbalance, insulin resistance, hypermetabolism, and malnutrition. Moreover, muscle wasting, known to develop in chronic kidney disease patients, is a harmful consequence of numerous complications associated with deteriorated renal function. Plenty of published data suggest that serum creatinine (SCr) reflects increased kidney damage and is also related to body weight. Based on the concept that urea and creatinine are nitrogenous end products of metabolism, the urea:creatinine ratio (UCR) could be applied but with limited clinical usability in case of kidney damage, hypovolemia, excessive, or protein intake, where UCR can be high and independent of catabolism. Recent data suggest that the sarcopenia index should be considered an alternative to serum creatinine. It is more reliable in estimating muscle mass than SCr. However, the optimal biomarker of catabolism is still an unresolved issue. The SCr is not a promising biomarker for renal function and muscle mass based on the influence of several factors. The present review highlights recent findings on the limits of SCr as a surrogate marker of renal function and the assessment modalities of nutritional status and muscle mass measurements.
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Estado Nutricional , Sarcopenia , Humanos , Creatinina , Sarcopenia/diagnóstico , Sarcopenia/etiologia , Ureia , Músculos , BiomarcadoresRESUMO
Cancer cachexia is commonly seen in patients with malignant tumors, which usually leads to poor life quality and negatively affects long-term prognosis and survival. Mitochondria dysfunction and enhanced autophagy are well-established to play an important role in skeletal muscle wasting. However, whether mitophagy is engaged in the pathogenesis of cancer cachexia requires further investigation. This study comprised a clinical study and animal experimentation. Clinical data such as CT images and laboratory results were obtained and analyzed. Then mice model of cancer cachexia and mitophagy inhibition were established. Data including skeletal muscle mass and function, mitochondria structure and function, inflammatory factors as well as ROS concentration. Mitophagy was enhanced in cancer cachexia patients with increased inflammatory factors. Greater disruption of skeletal muscle fiber and mitochondria structure were seen in cancer cachexia, with a higher level of inflammatory factors and ROS expression in skeletal muscle. Meanwhile, ATP production was undermined, indicating a close relationship with mitophagy, inflammation, and oxidative stress in the skeletal muscle of cancer cachexia mice models. In conclusion, mitophagy is activated in cancer cachexia and may play a role in skeletal muscle atrophy, and inflammation and oxidative stress might participate in mitophagy-related skeletal muscle injury.
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BACKGROUND: Cancer cachexia is a debilitating syndrome associated with marked body loss because of muscular atrophy and fat loss. There are several mechanisms contributing to the pathogenesis of cachexia. The presence of the tumor releases cytokines from inflammatory and immune cells, which play a significant role in activating and deactivating certain pathways associated with protein, carbohydrate, and lipid metabolism. This review focuses on various cascades involving an imbalance between protein synthesis and degradation in the skeletal muscles. OBJECTIVES: This study aimed to elucidate the mechanisms involved in skeletal muscle wasting phenomenon over the last few years. METHODS: This article briefly overviews different pathways responsible for muscle atrophy in cancer cachexia. Studies published up to April 2023 were included. Important findings and study contributions were chosen and compiled using several databases including PubMed, Google Scholar, Science Direct, and ClinicalTrials.gov using relevant keywords. RESULTS: Cancer cachexia is a complex disease involving multiple factors resulting in atrophy of skeletal muscles. Systemic inflammation, altered energy balance and carbohydrate metabolism, altered lipid and protein metabolism, and adipose tissue browning are some of the major culprits in cancer cachexia. Increased protein degradation and decreased protein synthesis lead to muscle atrophy. Changes in signaling pathway like ubiquitin-proteasome, autophagy, mTOR, AMPK, and IGF-1 also lead to muscle wasting. Physical exercise, nutritional supplementation, steroids, myostatin inhibitors, and interventions targeting on inflammation have been investigated to treat cancer cachexia. Some therapy showed positive results in preclinical and clinical settings, although more research on the efficacy and safety of the treatment should be done. CONCLUSION: Muscle atrophy in cancer cachexia is the result of multiple complex mechanisms; as a result, a lot more research has been done to describe the pathophysiology of the disease. Targeted therapy and multimodal interventions can improve clinical outcomes for patients.
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Caquexia , Neoplasias , Humanos , Caquexia/etiologia , Caquexia/terapia , Caquexia/metabolismo , Neoplasias/complicações , Neoplasias/patologia , Atrofia Muscular/etiologia , Atrofia Muscular/terapia , Atrofia Muscular/metabolismo , Músculo Esquelético/metabolismo , Inflamação/metabolismoRESUMO
BACKGROUND/AIMS: Myosteatosis implies impaired muscle quality. The aim of the study was to investigate the association of myosteatosis with other muscle abnormalities and its role in the prognosis of liver cirrhosis (LC). METHOD: Skeletal muscle index (SMI) and myosteatosis were measured by computed tomography. Myosteatosis was defined as muscle radiodensity and evaluated according to dry body mass index (BMI). Median values and interquartile range were used for continuous and count (percentage) for categorical variables. RESULTS: A total of 197 consecutive patients were included (age 61 (IQR 52-68); 67% male; MELD score 11 (interquartile range 7.5-16)). Myosteatosis was identified in 73.6% and sarcopenia in 44.6% of patients. Myosteatosis was positively associated with age (p = 0.024) and Child-Pugh (p = 0.017) and inversely associated with SMI (p = 0.026). Patients with myosteatosis exhibited lower 360-day survival (log-rank p = 0.001) compared to those without it. MELD (p < 0.001) and myosteatosis (p = 0.048) emerged as negative prognostic factors of survival in multivariate model. Individuals combining low muscle strength and impaired muscle quality and quantity displayed more advanced LC, impaired muscle performance, lower BMI (p < 0.001 each) and a three times higher mortality rate compared to those with low muscle quality alone. CONCLUSIONS: The presence of myosteatosis was associated with advanced age, low skeletal mass and more severe LC. Myosteatosis was associated with poor prognosis and may represent a prodromal phase of muscle degeneration before the development of sarcopenia.
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This review highlights some established and some more contemporary mechanisms responsible for heart failure (HF)-induced skeletal muscle wasting and weakness. We first describe the effects of HF on the relationship between protein synthesis and degradation rates, which determine muscle mass, the involvement of the satellite cells for continual muscle regeneration, and changes in myofiber calcium homeostasis linked to contractile dysfunction. We then highlight key mechanistic effects of both aerobic and resistance exercise training on skeletal muscle in HF and outline its application as a beneficial treatment. Overall, HF causes multiple impairments related to autophagy, anabolic-catabolic signaling, satellite cell proliferation, and calcium homeostasis, which together promote fiber atrophy, contractile dysfunction, and impaired regeneration. Although both wasting and weakness are partly rescued by aerobic and resistance exercise training in HF, the effects of satellite cell dynamics remain poorly explored.
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Cálcio , Insuficiência Cardíaca , Humanos , Cálcio/metabolismo , Atrofia Muscular/terapia , Atrofia Muscular/etiologia , Músculo Esquelético/metabolismo , Insuficiência Cardíaca/terapia , Insuficiência Cardíaca/metabolismo , Exercício Físico , RegeneraçãoRESUMO
Chronic Kidney Disease (CKD) is a global health burden with high mortality and health costs. CKD patients exhibit lower cardiorespiratory and muscular fitness, strongly associated with morbidity/mortality, which is exacerbated when they reach the need for renal replacement therapies (RRT). Muscle wasting in CKD has been associated with an inflammatory/oxidative status affecting the resident cells' microenvironment, decreasing repair capacity and leading to atrophy. Exercise may help counteracting such effects; however, the molecular mechanisms remain uncertain. Thus, trying to pinpoint and understand these mechanisms is of particular interest. This review will start with a general background about myogenesis, followed by an overview of the impact of redox imbalance as a mechanism of muscle wasting in CKD, with focus on the modulatory effect of exercise on the skeletal muscle microenvironment.
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Músculo Esquelético , Insuficiência Renal Crônica , Humanos , Músculo Esquelético/metabolismo , Insuficiência Renal Crônica/metabolismo , Atrofia Muscular/metabolismo , Oxirredução , Exercício FísicoRESUMO
Aim: Nutrition is an important part of the care of patients with chronic kidney disease (CKD). However, there is limited clinical research on the skeletal muscle nutrition of patients with CKD. We carried out this study to find out whether a low-protein diet supplemented with ketoacids (LPD + KA) could improve muscle wasting in patients with CKD. Methods: Patients were enrolled in this non-blind, parallel-group, randomized trial assessing the nutritional status of CKD, randomly assigned to either the LPD + KA group or conventional LPD group. Blood samples such as Hemoglobin, Cystatin C, Creatinine, BUN, Albumin, Pre- Albumin, Glycerin Trilaurate, and Cholesterol were measured at baseline and every 3 months. The parameters of skeletal muscle and other body composition were assessed before and after dietary intervention for 12 months. Results: A total of 58 patients with CKD completed the study and were available for further analysis. The hemoglobin and albumin were observed to be markedly improved in the LPD + KA group during the follow-up as compared to baseline. Body mass index and total body water index of both groups were increased upon follow-up but the increase in the LPD + KA group was comparatively higher. Moreover, an increase in body fat%, skeletal muscle mass index, and appendicular skeletal muscle mass index was observed in both groups between baseline and follow-up, but it was statistically insignificant. Conclusion: This study did not find a significant improvement of KAs on muscle wasting, and a long time or more indices study may need to find the effects of the LPD + KA diets. Clinical trial registration: [www.ClinicalTrials.gov], identifier [NCT02568020].
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Calciprotein particles (CPPs) are tiny mineral-protein aggregates consisting of calcium-phosphate and fetuin-A. Recent studies have suggested that CPPs may contribute to the pathogenesis of chronic inflammation and arteriosclerosis. Reduced skeletal muscle mass and strength reportedly contribute independently to increased serum phosphate levels. This finding suggests that reduced skeletal muscle mass and strength can endogenously induce an increase in circulating CPP levels. Therefore, we investigated the potential association between circulating CPP levels and skeletal muscle mass and strength in middle-aged and older adults. One hundred eighty-two middle-aged and older adults (age, 46-83 years) were included in this cross-sectional study (UMIN000034741). Circulating CPP levels were measured using the gel filtration method. Appendicular skeletal muscle mass was assessed using multifrequency bioelectrical impedance analysis with a tetrapolar eight-point tactile electrode system. The skeletal muscle mass index was calculated from appendicular skeletal muscle mass and height. Handgrip and knee extension strengths were used as measures of skeletal muscle strength. The skeletal muscle mass index was negatively correlated with circulating CPP levels (r = -0.31; P < 0.05). This association remained significant after adjustment for potential covariates (ß = -0.34; P < 0.05). In contrast, skeletal muscle strength, represented by handgrip strength and knee extension strength, was not significantly associated with circulating CPP levels. In middle-aged and older adults, a lower skeletal muscle mass index was independently associated with higher circulating CPP levels. The present results suggest that maintaining skeletal muscle mass may prevent an increase in circulating CPP levels.
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Força da Mão , Músculo Esquelético , Idoso , Idoso de 80 Anos ou mais , Estatura , Estudos Transversais , Força da Mão/fisiologia , Humanos , Pessoa de Meia-Idade , Força Muscular/fisiologia , Músculo Esquelético/fisiologiaRESUMO
Transforming growth factor-beta (TGF-ß) is part of a family of molecules that is present in many body tissues and performs many different functions. Evidence has been obtained from mice and human cancer patients with bony metastases and non-metastatic disease, as well as pediatric burn patients, that inflammation leads to bone resorption and release of TGF-ß from the bone matrix with paracrine effects on muscle protein balance, possibly mediated by the generation of reactive oxygen species. Whether immobilization, which confounds the etiology of bone resorption in burn injury, also leads to the release of TGF-ß from bone contributing to muscle wasting in other conditions is unclear. The use of anti-resorptive therapy in both metastatic cancer patients and pediatric burn patients has been successful in the prevention of muscle wasting, thereby creating an additional therapeutic niche for this class of drugs. The liberation of TGF-ß may be one way in which bone helps to control muscle mass, but further investigation will be necessary to assess whether the rate of bone resorption is the determining factor for the release of TGF-ß. Moreover, whether different resorptive conditions, such as immobilization and hyperparathyroidism, also involve TGF-ß release in the pathogenesis of muscle wasting needs to be investigated.
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Reabsorção Óssea/patologia , Proteínas Musculares/metabolismo , Atrofia Muscular/patologia , Espécies Reativas de Oxigênio/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Reabsorção Óssea/metabolismo , Humanos , Atrofia Muscular/metabolismoRESUMO
BACKGROUND: Low skeletal muscle area or density, such as myosteatosis, identified on computed tomography (CT) is associated with poor prognosis in patients with cardiovascular diseases. However, there is a lack of evidence regarding the clinical process of skeletal muscle decline as a short-term change during acute care settings. This study focused on the use of routine CT imaging for aortic disease management and investigated the changes in skeletal muscle before and after acute care. METHODS: This prospective study included 123 patients who underwent abdominal CT before and after acute care. The all-abdominal and each abdominal muscle areas were divided into eight parts (e.g. rectus abdominis, psoas, and erector spine), and their areas and densities were measured at the third lumbar vertebra level after the patients were discharged and de-identified with blinding to avoid measurement bias. Short physical performance battery (SPPB) was measured at the start and end of in-hospital cardiac rehabilitation. A generalized linear model with patients as random effects was made to investigate skeletal muscle loss during acute care. Multivariate linear regression analysis was also used to assess the relationship between the change in skeletal muscle during acute care and SPPB during in-hospital cardiac rehabilitation. RESULTS: The median age of the patients was 70 (interquartile: 58-77) years, and 69.9% (86/123) were men. The median day between acute care from the day of surgery or hospital admission and follow-up CT was 7 (interquartile: 3-8) days. Overall muscle density declined after acute care (estimate value: -3.640, 95% confidence interval [CI]: -4.538 to -2.741), and each abdominal muscle density consistently declined (interaction: F value = 0.099, P = 0.998). In contrast, there was no significant change in the overall muscle area (estimate value: -0.863, 95% CI: -2.925 to 1.200). Changes in the muscle area were different for each skeletal muscle (interaction: F value = 2.142, P = 0.037), and only the erector spine muscle significantly declined (estimate value: -1.836, 95% CI: -2.507 to -1.165). After adjusting for confounding factors, a greater decline in muscle density was associated with lower recovery score on SPPB (ß = 0.296, 95% CI: 0.066 to 0.400). CONCLUSIONS: Muscle density consistently declined after acute care, especially the erector spine muscles, which also significantly decreased in size. A higher decline in muscle density was associated with a slower recovery of physical function during in-hospital cardiac rehabilitation in patients with aortic diseases.
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Doenças da Aorta , Atrofia Muscular , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Estudos Prospectivos , Recuperação de Função FisiológicaRESUMO
BACKGROUND: Considerable controversies exist regarding the severity of skeletal muscle wasting (SMW) during neoadjuvant therapy (NAT) and its impact on therapeutic outcomes in patients with esophageal or esophagogastric junction cancer (EC/EGJC). This systematic review and meta-analysis aimed to resolve these issues. Particularly, the prognostic value of SMW during NAT was compared to pre-NAT and pre-surgery sarcopenia status. METHODS: We searched PubMed, Embase, and Cochrane Library databases through October 13th, 2021 to identify cohort studies focusing on SMW during NAT and therapeutic outcomes in EC/EGJC patients. Both neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy were studied. A meta-analysis was conducted to quantify SMW and increased sarcopenia during NAT. Therapeutic outcomes include perioperative morbidities and survival profiles. A separate meta-analysis investigating the impacts of pre-NAT/pre-surgery sarcopenia on therapeutic outcomes was synchronously performed. RESULTS: Twenty-five studies with 2706 participants were included in this review. The pooled SMW during NAT were -2.47 cm2/m2 in skeletal muscle index and -0.23 cm2/m2 in psoas muscle index, with wasting proportion reaching 4.44%. The pooled prevalence rate of sarcopenia increased from 53.1% before NAT to 65.8% before surgery. Neoadjuvant chemoradiotherapy, advanced age, and being male were identified as risk factors for severe SMW during NAT. Notably, severe SMW during NAT showed a greater hazard ratio (HR) than pre-NAT and pre-surgery sarcopenia in predicting overall survival (HR 1.92, P < 0.001; HR 1.17, P = 0.036; and HR 1.28, P = 0.011, respectively) and recurrence-free survival (HR 1.51, P = 0.002; HR 1.27, P = 0.008; and HR 1.38, P = 0.006, respectively). However, severe SMW during NAT was not significantly associated with perioperative morbidities. CONCLUSIONS: SMW during NAT is a novel prognosticator that is different from sarcopenia for poor survival in EC/EGJC patients. Interventions aiming at maintaining skeletal muscle during NAT are anticipated to promote therapeutic outcomes.
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Neoplasias Esofágicas , Sarcopenia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Junção Esofagogástrica , Humanos , Masculino , Músculo Esquelético/patologia , Terapia Neoadjuvante , Prognóstico , Músculos Psoas , Sarcopenia/etiologia , Taxa de SobrevidaRESUMO
To investigate whether exogenous melatonin (MLT) could alleviate skeletal muscle wasting by regulating hypothalamic neuropeptides expression. Adult male Sprague Dawley rats were intraperitoneally injected with lipopolysaccharide (LPS) (10 mg/kg), followed by MLT (30 mg/kg/day) or saline for 3 days. Hypothalamic tissues and skeletal muscle were obtained on day 3. Skeletal muscle wasting was measured by the mRNA expression of two E3 ubiquitin ligases, muscle atrophy F-box and muscle ring finger 1 as well as 3-methylhistidine (3-MH) and tyrosine release. Three hypothalamic neuropeptides (POMC, AgRP, CART) expression were detected in all groups. POMC expression knockdown was achieved by ARC injection of lentiviruses containing shRNA against POMC. Two weeks after ARC viruses injection, rats were i.p. injected with LPS (10 mg/kg) followed by MLT (30 mg/kg/day) or saline for 3 days. Brain tissues were harvested for immunostaining. In septic rats, 3-MH, tyrosine release and muscle atrophic gene expression were significantly decreased in MLT treated group. POMC and CART expression were lower while AgRP expression was higher in MLT treated group. Furthermore, in septic rats treated with MLT, muscle wasting in those with lower expression of neuropeptide POMC did not differ from those with normal POMC expression. Exogenous MLT could alleviate skeletal muscle wasting in septic rats by regulating hypothalamic neuropeptides.
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Endotoxemia , Melatonina , Neuropeptídeos , Animais , Endotoxemia/metabolismo , Endotoxemia/patologia , Hipotálamo/metabolismo , Masculino , Melatonina/metabolismo , Melatonina/farmacologia , Melatonina/uso terapêutico , Músculo Esquelético/metabolismo , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/metabolismo , Neuropeptídeos/metabolismo , Pró-Opiomelanocortina , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND AND AIMS: We hypothesized that in long-term immobilized intensive care unit (ICU) patients, both the quantity and quality of protein nutrition are vital in supporting muscle mass maintenance. Hence, the aim of this secondary analysis of our recently performed RCT was to calculate the intake of individual amino acids and to evaluate the potential associations of amino acid patterns with muscle mass loss during the ICU stay. METHODS: Clinical and nutritional data were collected from a recent RCT conducted in long-term immobilized, critically ill patients receiving medical nutrition therapy with either 1.8 g (interventional group) or 1.2 g (standard group) of protein/amino acids per kg body weight per day over 4 weeks. Intake of the individual amino acids as well as the sum scores of the indispensable, conditionally indispensable, and dispensable amino acids were calculated for all patients, both group specific (n = 21 in each group) and in total (n = 42), based on the detailed nutrition protocols; inter-group differences were analyzed by t-tests. Linear regression models were used to test the effects of individual amino acids and the sum scores on the extent of skeletal muscle loss by measuring the quadriceps muscle layer thickness during the study period. The significance level was adjusted for multiple testing according to the Bonferroni procedure (α = 0.002). RESULTS: In both groups, the proportion of indispensable amino acids was approximately 41% of the total exogenous protein supply, with the proportion of enteral administration slightly over 50%. The intake of conditionally indispensable amino acids (glutamine, tyrosine, cysteine, histidine, and arginine) accounted for 17% and 18% of the total amino acids in the interventional and standard groups, respectively; glutamine (5% of total amino acids) was exclusively administered enterally. The intake of dispensable amino acid varied widely, with glutamic acid, proline, and asparagine/aspartic acid representing the highest proportions (10%, 8%, and 8% of total amino acids, respectively). For all amino acids, no statistically significant association was observed between the quantitative intake and the skeletal muscle changes after terminating the intervention phase. CONCLUSION: This secondary analysis of the RCT conducted in routine clinical practice did not support our working hypothesis that the amino acid patterns of medical nutrition therapy have a statistically significant impact on the skeletal muscle loss in long-term immobilized ICU patients. Due to the limited variety of enteral/parenteral products used in this single-center study, the calculated amino acid patterns showed only small differences. Larger multi-center trials with adequate power are needed to evaluate the potential effects of the individual amino acids or defined amino acid patterns on the muscle protein metabolism in further detail. TRIAL REGISTRATION: German Clinical Trials Register (http://www.drks.de); DRKS-ID: DRKS00013594.
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Unidades de Terapia Intensiva , Nutrição Parenteral , Adulto , Aminoácidos , Estado Terminal/terapia , Humanos , Músculos , Nutrição Parenteral/métodosRESUMO
Cancer cachexia is a kind of whole-body metabolic disorder syndrome accompanied by severe wasting of muscle tissue in which cancer exosomes may be involved. Analysis of clinical samples showed that the serum exosome concentrations were correlated with the development of cancer cachexia. Exosomes secreted by C26 cells could decrease the diameter of C2C12 myotubes in vitro and decrease mouse muscle strength and tibialis anterior (TA) muscle weight in vivo. GW4869, an inhibitor of exosome excretion, ameliorated muscle wasting in C26 tumor-bearing mice. MicroRNA (miRNA) sequencing (miRNA-seq) analysis suggested that miR-195a-5p and miR-125b-1-3p were richer in C26 exosomes than in exosomes secreted from MC38 cells (non-cachexic). Both miR-195a-5p and miR-125b-1-3p mimics could induce atrophy of C2C12 myoblasts. Downregulation of Bcl-2 and activation of the apoptotic signaling pathway were observed in C2C12 myoblasts transfected with miR-195a-5p and miR-125b-1-3p mimics, in the gastrocnemius muscle of C26 tumor-bearing mice and in the TA muscle injected with C26 exosomes. Results of dual-luciferase assay confirmed the targeting of miR-195a-5p/miR-125b-1-3p to Bcl-2. Overexpression of Bcl-2 successfully reversed atrophy of C2C12 myoblasts induced by the two miRNA mimics. These results suggested that cancer exosome enriched miRNAs might induce muscle atrophy by targeting Bcl-2-mediated apoptosis.
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BACKGROUND: Skeletal muscle wasting (SMW) in cancer patients is associated with increased morbidity, mortality, treatment intolerance and discontinuation, and poor quality of life. This is particularly true for patients with pancreatic ductal adenocarcinoma (PDAC), as over 85% experience SMW, which is responsible for ~30% of patient deaths. While the established paradigm to explain SMW posits that muscle catabolism from systemic inflammation and nutritional deficiencies, the cause of death, and the cellular and molecular mechanisms responsible remain to be elucidated. To address this, we investigated the relationship between tumour burden and survival in the KCKO murine PDAC model. METHODS: Female C57BL/6J mice 6-8 weeks of age underwent orthotopic injection with KCKO-luc tumour cells. Solid tumour was verified on Day 5, post-tumour inoculation. In vivo, longitudinal lean mass and tumour burden were assessed via dual-energy X-ray absorptiometry and IVIS imaging, respectively, and total body weight was assessed, weekly. Animals were sacrificed at a designated end point of 'failure to thrive'. After sacrifice, lower limb hind muscles were harvested for histology and RNA extraction. RESULTS: We found a strong correlation between primary tumour size and survival (r2 = 0.83, P < 0.0001). A significant decrease in lower limb lean mass was first detected at Day 38 post-implantation vs. no tumour controls (NTCs) (P < 0.0001). SMW was confirmed by histology, which demonstrated a 38%, 32.7%, and 39.9% decrease in fibre size of extensor digitorum longus, soleus, and tibialis anterior muscles, respectively, in PDAC mice vs. NTC (P < 0.002). Histology also revealed a 67.6% increase in haematopoietic cells within the muscle of PDAC mice when compared with NTC. Bulk RNAseq on muscles from PDAC mice vs. NTC revealed significant increases in c/ebpß/Δ, il-1, il-6, and tnf gene expression. Pathway analyses to identify potential upstream factors revealed increased adipogenic gene expression, including a four-fold increase in igfbp-3. Histomorphometry of Oil Red-O staining for fat content in tibialis anterior muscles demonstrated a 95.5% increase in positively stained fibres from PDAC mice vs. NTC. CONCLUSIONS: Together, these findings support a novel model of PDAC-associated SMW and mortality in which systemic inflammation leads to inflammatory cell infiltration into skeletal muscle with up-regulated myocellular lipids.