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Cancer cachexia, and its associated complications, represent a large and currently untreatable roadblock to effective cancer management. Many potential therapies have been proposed and tested-including appetite stimulants, targeted cytokine blockers, and nutritional supplementation-yet highly effective therapies are lacking. Innovative approaches to treating cancer cachexia are needed. Members of the Kruppel-like factor (KLF) family play wide-ranging and important roles in the development, maintenance, and metabolism of skeletal muscle. Within the KLF family, we identified KLF10 upregulation in a multitude of wasting contexts-including in pancreatic, lung, and colon cancer mouse models as well as in human patients. We subsequently interrogated loss-of-function of KLF10 as a potential strategy to mitigate cancer associated muscle wasting. In vivo studies leveraging orthotopic implantation of pancreas cancer cells into wild-type and KLF10 KO mice revealed significant preservation of lean mass and robust suppression of pro-atrophy muscle-specific ubiquitin ligases Trim63 and Fbxo32, as well as other factors implicated in atrophy, calcium signaling, and autophagy. Bioinformatics analyses identified Transforming growth factor beta (TGF-ß), a known inducer of KLF10 and cachexia promoting factor, as a key upstream regulator of KLF10. We provide direct in vivo evidence that KLF10 KO mice are resistant to the atrophic effects of TGF-ß. ChIP-based binding studies demonstrated direct binding to Trim63, a known wasting-associated atrogene. Taken together, we report a critical role for the TGF-ß/KLF10 axis in the etiology of pancreatic cancer-associated muscle wasting and highlight the utility of targeting KLF10 as a strategy to prevent muscle wasting and limit cancer-associated cachexia.
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Neoplasias Pancreáticas , Factor de Crecimiento Transformador beta , Humanos , Ratones , Animales , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Caquexia/genética , Atrofia Muscular/genética , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Músculo Esquelético/metabolismo , Factores de Transcripción de la Respuesta de Crecimiento Precoz/genética , Factores de Transcripción de la Respuesta de Crecimiento Precoz/metabolismoRESUMEN
Cancer cachexia, the unintentional loss of lean mass, contributes to functional dependency, poor treatment outcomes, and decreased survival. Although its pathogenicity is multifactorial, metabolic dysfunction remains a hallmark of cachexia. However, significant knowledge gaps exist in understanding the role of skeletal muscle lipid metabolism and dynamics in this condition. We examined skeletal muscle metabolic dysfunction, intramyocellular lipid droplet (LD) content, LD morphology and subcellular distribution, and LD-mitochondrial interactions using the Lewis lung carcinoma (LLC) murine model of cachexia. C57/BL6 male mice (n = 20) were implanted with LLC cells (106) in the right flank or underwent PBS sham injections. Skeletal muscle was excised for transmission electron microscopy (TEM; soleus), oil red O/lipid staining [tibialis anterior (TA)], and protein (gastrocnemius). LLC mice had a greater number (232%; P = 0.006) and size (130%; P = 0.023) of intramyocellular LDs further supported by increased oil-red O positive (87%; P = 0.0109) and "very high" oil-red O positive (178%; P = 0.0002) fibers compared with controls and this was inversely correlated with fiber size (R2 = 0.5294; P < 0.0001). Morphological analyses of LDs show increased elongation and complexity [aspect ratio: intermyofibrillar (IMF) = 9%, P = 0.046) with decreases in circularity [circularity: subsarcolemmal (SS) = 6%, P = 0.042] or roundness (roundness: whole = 10%, P = 0.033; IMF = 8%, P = 0.038) as well as decreased LD-mitochondria touch (-15%; P = 0.006), contact length (-38%; P = 0.036), and relative contact (86%; P = 0.004). Furthermore, dysregulation in lipid metabolism (adiponectin, CPT1b) and LD-associated proteins, perilipin-2 and perilipin-5, in cachectic muscle (P < 0.05) were observed. Collectively, we provide evidence that skeletal muscle myosteatosis, altered LD morphology, and decreased LD-mitochondrial interactions occur in a preclinical model of cancer cachexia.NEW & NOTEWORTHY We sought to advance our understanding of skeletal muscle lipid metabolism and dynamics in cancer cachexia. Cachexia increased the number and size of intramyocellular lipid droplets (LDs). Furthermore, decreases in LD-mitochondrial touch, contact length, and relative contact along with increased LD shape complexity with decreases in circularity and roundness. Dysregulation in lipid metabolism and LD-associated proteins was also documented. Collectively, we show that myosteatosis, altered LD morphology, and decreased LD-mitochondrial interactions occur in cancer cachexia.
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Caquexia , Carcinoma Pulmonar de Lewis , Gotas Lipídicas , Ratones Endogámicos C57BL , Músculo Esquelético , Animales , Caquexia/metabolismo , Caquexia/patología , Caquexia/etiología , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patología , Carcinoma Pulmonar de Lewis/complicaciones , Gotas Lipídicas/metabolismo , Gotas Lipídicas/patología , Ratones , Metabolismo de los Lípidos , Mitocondrias Musculares/metabolismo , Mitocondrias Musculares/patología , Mitocondrias Musculares/ultraestructura , Mitocondrias/metabolismo , Mitocondrias/patología , Mitocondrias/ultraestructuraRESUMEN
Hypertonic dehydration is associated with muscle wasting and synthesis of organic osmolytes. We recently showed a metabolic shift to amino acid production and urea cycle activation in coronavirus-2019 (COVID-19), consistent with the aestivation response. The aim of the present investigation was to validate the metabolic shift and development of long-term physical outcomes in the non-COVID cohort of the Biobanque Québécoise de la COVID-19 (BQC19). We included 824 patients from BQC19, where 571 patients had data of dehydration in the form of estimated osmolality (eOSM = 2Na + 2K + glucose + urea), and 284 patients had metabolome data and long-term follow-up. We correlated the degree of dehydration to mortality, invasive mechanical ventilation, acute kidney injury, and long-term symptoms. As found in the COVID cohort, higher eOSM correlated with a higher proportion of urea and glucose of total eOSM, and an enrichment of amino acids compared with other metabolites. Sex-stratified analysis indicated that women may show a weaker aestivation response. More severe dehydration was associated with mortality, invasive mechanical ventilation, and acute kidney injury during the acute illness. Importantly, more severe dehydration was associated with physical long-term symptoms but not mental long-term symptoms after adjustment for age, sex, and disease severity. Patients with water deficit in the form of increased eOSM tend to have more severe disease and experience more physical symptoms after an acute episode of care. This is associated with amino acid and urea production, indicating dehydration-induced muscle wasting.NEW & NOTEWORTHY We have previously shown that humans exhibit an aestivation-like response where dehydration leads to a metabolic shift to urea synthesis, which is associated with long-term weakness indicating muscle wasting. In the present study, we validate this response in a new cohort and present a deeper metabolomic analysis and pathway analysis. Finally, we present a sex-stratified analysis suggesting weaker aestivation in women. However, women show less dehydration, so the association warrants further study.
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COVID-19 , Deshidratación , Metaboloma , Humanos , Femenino , Masculino , Persona de Mediana Edad , Deshidratación/metabolismo , COVID-19/metabolismo , COVID-19/complicaciones , Anciano , Metabolómica/métodos , Respiración Artificial , Lesión Renal Aguda/metabolismo , Adulto , SARS-CoV-2 , Estudios de Cohortes , Aminoácidos/metabolismo , Aminoácidos/sangre , Urea/metabolismo , Urea/sangre , Concentración OsmolarRESUMEN
Cancer cachexia-associated muscle wasting as a multifactorial wasting syndrome, is an important factor affecting the long-term survival rate of tumor patients. Photobiomodulation therapy (PBMT) has emerged as a promising tool to cure and prevent many diseases. However, the effect of PBMT on skeletal muscle atrophy during cancer progression has not been fully demonstrated yet. Here, we found PBMT alleviated the atrophy of myotube diameter induced by cancer cells in vitro, and prevented cancer-associated muscle atrophy in mice bearing tumor. Mechanistically, the alleviation of muscle wasting by PBMT was found to be involved in inhibiting E3 ubiquitin ligases MAFbx and MuRF-1. In addition, transcriptomic analysis using RNA-seq and GSEA revealed that PI3K/AKT pathway might be involved in PBMT-prevented muscle cachexia. Next, we showed the protective effect of PBMT against muscle cachexia was totally blocked by AKT inhibitor in vitro and in vivo. Moreover, PBMT-activated AKT promoted FoxO3a phosphorylation and thus inhibiting the nucleus entry of FoxO3a. Lastly, in cisplatin-treated muscle cachexia model, PBMT had also been shown to ameliorate muscle atrophy through enhancing PI3K/AKT pathway to suppress MAFbx and MuRF-1 expression. These novel findings revealed that PBMT could be a promising therapeutic approach in treating muscle cachexia induced by cancer.
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Caquexia , Proteína Forkhead Box O3 , Enfermedades Musculares , Neoplasias , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Síndrome Debilitante , Caquexia/etiología , Caquexia/metabolismo , Caquexia/terapia , Enfermedades Musculares/etiología , Enfermedades Musculares/metabolismo , Enfermedades Musculares/terapia , Neoplasias/complicaciones , Redes y Vías Metabólicas , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Síndrome Debilitante/etiología , Síndrome Debilitante/metabolismo , Síndrome Debilitante/terapia , Animales , Modelos Animales de Enfermedad , Ratones , Línea Celular , Masculino , Ratones Endogámicos BALB C , Perfilación de la Expresión GénicaRESUMEN
Cancer cachexia (CC) is a debilitating syndrome that affects 50-80% of cancer patients, varying in incidence by cancer type and significantly diminishing their quality of life. This multifactorial syndrome is characterized by muscle and fat loss, systemic inflammation, and metabolic imbalance. Extracellular vesicles (EVs), including exosomes and microvesicles, play a crucial role in the progression of CC. These vesicles, produced by cancer cells and others within the tumor environment, facilitate intercellular communication by transferring proteins, lipids, and nucleic acids. A comprehensive review of the literature from databases such as PubMed, Scopus, and Web of Science reveals insights into the formation, release, and uptake of EVs in CC, underscoring their potential as diagnostic and prognostic biomarkers. The review also explores therapeutic strategies targeting EVs, which include modifying their release and content, utilizing them for drug delivery, genetically altering their contents, and inhibiting key cachexia pathways. Understanding the role of EVs in CC opens new avenues for diagnostic and therapeutic approaches, potentially mitigating the syndrome's impact on patient survival and quality of life.
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Caquexia , Vesículas Extracelulares , Neoplasias , Humanos , Caquexia/metabolismo , Caquexia/etiología , Caquexia/terapia , Vesículas Extracelulares/metabolismo , Neoplasias/complicaciones , Neoplasias/patología , Neoplasias/metabolismo , AnimalesRESUMEN
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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BACKGROUND AND AIMS: Low serum 25-hydroxyvitamin D (25 [OH]D) levels have been associated with sarcopenia, frailty, and risk of cardiovascular disease, whereas high levels negatively impact clinical outcomes. We determined optimal serum 25(OH)D concentrations to minimise the probability of sarcopenia in patients with heart failure (HF) by examining the dose-dependent relationship between serum 25(OH)D levels and sarcopenia. METHODS AND RESULTS: We enrolled 461 consecutive patients with HF (mean age, 72 ± 15 years; 39% female) who underwent dual-energy X-ray absorptiometry. Serum 25(OH)D levels were measured using a chemiluminescence immunoassay. Sarcopenia was diagnosed according to the 2019 Asian Working Group for Sarcopenia criteria. Overall, 49% of enrolled patients were diagnosed with sarcopenia. Adjusted logistic regression with restricted cubic spline function revealed that the odds ratio (OR) of sarcopenia increased in patients with HF presenting serum 25(OH)D levels <14.6 ng/ml or > 31.4 ng/ml, reaching the lowest OR at â¼20 ng/ml. Multivariate logistic regression revealed that a serum 25(OH)D level below 14.6 ng/mL was independently associated with the presence of sarcopenia (adjusted OR: 2.16, 95% confidence interval [CI]: 1.24-3.78). Incorporating serum 25(OH)D levels <14.6 ng/ml, but not <20.0 ng/ml, in the baseline model improved continuous net reclassification (0.334, 95% CI: 0.122-0.546) in patients with HF. CONCLUSION: A U-shaped relationship exists between serum 25(OH)D levels and sarcopenia probability in patients with HF. Maintaining serum 25(OH)D levels between 14.6 and 31.4 ng/ml may help prevent sarcopenia in patients with HF.
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Insuficiencia Cardíaca , Sarcopenia , Deficiencia de Vitamina D , Vitamina D/análogos & derivados , Humanos , Femenino , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Masculino , Sarcopenia/diagnóstico , Sarcopenia/epidemiología , Sarcopenia/prevención & controlRESUMEN
BACKGROUND: Acute muscle wasting is common in critically ill patients, and this can lead to unfavorable clinical outcomes. The aim of this study was to identify factors associated with muscle wasting and to investigate the association between skeletal muscle wasting and prolonged hospital stay in critically ill patients with acute brain injury. METHODS: This single-center prospective observational study was conducted in critically ill patients with acute brain injury who stayed in the intensive care unit for at least 1 week. The rectus femoris cross-sectional area was measured via ultrasound at baseline and a week after the first assessment. Univariate and multivariate logistic regression analyses were performed to identify factors that predicted prolonged hospital stay. RESULTS: A total of 86 patients were included in the study. Their mean age was 49.4 ± 16.9 years, 57% were male, and 46.5% had an admission diagnosis of subarachnoid hemorrhage. The percentage change in the rectus femoris cross-sectional area was 15.8% (95% confidence interval [CI] - 19.8% to - 12.0%; p < 0.001), and 57% of all patients had acute muscle wasting. According to the univariate analysis, there was a significant association between prolonged hospital stay and acute muscle wasting (odds ratio [OR] 3.677; 95% CI 1.487-9.043; p = 0.005), mechanical ventilation status (OR 3.600; 95% CI 1.455-8.904; p = 0.006), and Glasgow Coma Scale score (OR 0.888; 95% CI 0.808-0.976; p = 0.014) at intensive care unit admission. The multivariate analysis demonstrated that acute muscle wasting (OR 3.449; 95% CI 1.344-8.853; p = 0.010) was an independent risk factor for prolonged hospital stay. CONCLUSIONS: There was considerable muscle wasting in critically ill patients with brain injuries over a 1-week period. Acute muscle wasting was associated with prolonged hospital stay in critically ill patients with acute brain injury.
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The gut microbiota plays a pivotal role in maintaining the dynamic balance of intestinal epithelial and immune cells, crucial for overall organ homeostasis. Dysfunctions in these intricate relationships can lead to inflammation and contribute to the pathogenesis of various diseases. Recent findings uncovered the existence of a gut-muscle axis, revealing how alterations in the gut microbiota can disrupt regulatory mechanisms in muscular and adipose tissues, triggering immune-mediated inflammation. In the context of Duchenne muscular dystrophy (DMD), alterations in intestinal permeability stand as a potential origin of molecules that could trigger muscle degeneration via various pathways. Metabolites produced by gut bacteria, or fragments of bacteria themselves, may have the ability to migrate from the gut into the bloodstream and ultimately infiltrate distant muscle tissues, exacerbating localized pathologies. These insights highlight alternative pathological pathways in DMD beyond the musculoskeletal system, paving the way for nutraceutical supplementation as a potential adjuvant therapy. Understanding the complex interplay between the gut microbiota, immune system, and muscular health offers new perspectives for therapeutic interventions beyond conventional approaches to efficiently counteract the multifaceted nature of DMD.
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Microbioma Gastrointestinal , Músculo Esquelético , Distrofia Muscular de Duchenne , Distrofia Muscular de Duchenne/microbiología , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patología , Humanos , Animales , Músculo Esquelético/metabolismo , Músculo Esquelético/microbiologíaRESUMEN
Breast cancer (BC) stands out as the most commonly type of cancer diagnosed in women worldwide, and chemotherapy, a key component of treatment, exacerbates cancer-induced skeletal muscle wasting, contributing to adverse health outcomes. Notably, the impact of chemotherapy on skeletal muscle seems to surpass that of the cancer itself, with inflammation identified as a common trigger for muscle wasting in both contexts. In skeletal muscle, pro-inflammatory cytokines modulate pathways crucial for the delicate balance between protein synthesis and breakdown, as well as satellite cell activation and myonuclear accretion. Physical exercise consistently emerges as a crucial therapeutic strategy to counteract cancer and chemotherapy-induced muscle wasting, ultimately enhancing patients' quality of life. However, a "one size fits all" approach does not apply to the prescription of exercise for BC patients, with factors such as age, menopause and comorbidities influencing the response to exercise. Hence, tailored exercise regimens, considering factors such as duration, frequency, intensity, and type, are essential to maximize efficacy in mitigating muscle wasting and improving disease outcomes. Despite the well-established anti-inflammatory role of aerobic exercise, resistance exercise proves equally or more beneficial in terms of mass and strength gain, as well as enhancing quality of life. This review comprehensively explores the molecular pathways affected by distinct exercise regimens in the skeletal muscle of cancer patients during chemotherapy, providing critical insights for precise exercise implementation to prevent skeletal muscle wasting.
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Neoplasias de la Mama , Ejercicio Físico , Músculo Esquelético , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Femenino , Músculo Esquelético/metabolismo , Músculo Esquelético/efectos de los fármacos , Calidad de Vida , Terapia por Ejercicio/métodos , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Atrofia Muscular/etiología , Atrofia Muscular/metabolismoRESUMEN
BACKGROUND AND AIMS: Muscle wasting results in weakness for patients with critical illness. We aim to explore ultrasound-derived rates of change in skeletal muscle in the intensive care unit (ICU) and following discharge to the post-ICU ward. DESIGN: Post hoc analysis of a multicentre randomised controlled trial of functional-electrical stimulated cycling, recumbent cycling, and usual care delivered in intensive care. METHOD: Participants underwent ultrasound assessment of rectus femoris at ICU admission, weekly in the ICU, upon awakening, ICU discharge, and hospital discharge. The primary outcome was rate of change in rectus femoris cross-sectional area (ΔRFCSA) in mm2/day in the ICU (enrolment to ICU discharge) and in the post-ICU ward (ICU discharge to hospital discharge). Secondary outcomes included rate of change in echo intensity (ΔEI), standard deviation of echo intensity (ΔEISD), and the intervention effect on ultrasound measures. Echo intensity is a quantitative assessment of muscle quality. Elevated echo intensity may indicate fluid infiltration, adipose tissue, and reduced muscle quality. RESULTS: 154 participants were included (mean age: 58 ± 15 years, 34% female). Rectus femoris cross-sectional area declined in the ICU (-4 mm2/day [95% confidence interval {CI}: -9 to 1]) and declined further in the ward (-9 mm2/day [95% CI: -14 to -3]) with a mean difference between ICU and ward of -5 mm2/day ([95% CI: -2, to 11]; p = 0.1396). There was a nonsignificant difference in ΔEI between in-ICU and the post-ICU ward of 1.2 ([95% CI: -0.1 to 2.6]; p = 0.0755), a statistically significant difference in ΔEISD between in-ICU and in the post-ICU ward of 1.0 ([95% CI, 0.5 to 1.5]; p = 0.0003), and no difference in rate of change in rectus femoris cross-sectional area between groups in intensive care (p = 0.411) or at hospital discharge (p = 0.1309). CONCLUSIONS: Muscle wasting occurs in critical illness throughout the hospital admission. The average rate of loss in muscle cross-sectional area does not slow after ICU discharge, even with active rehabilitation.
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Aim and background: Sarcopenia is a substantial contributor to intensive care unit (ICU)-acquired weakness and is associated with significant short- and long-term outcomes. It can, however, be mitigated by providing appropriate nutrition. Indirect calorimetry (IC) is believed to be the gold standard in determining caloric targets in the dynamic environment of critical illness. We conducted this study to compare the effect of IC vs weight-based (25 kcal/kg/day) feeding on quadriceps muscle thickness (QMT) by ultrasound in critically ill patients. Materials and methods: A prospective study was conducted on 60 mechanically ventilated patients randomized to two groups [weight-based equation (WBE) group or the IC group] in medical ICU after obtaining institutional ethics committee approval, and fed accordingly. The right QMT measurement using ultrasound and caloric targets were documented on day 1, 3 and 7 and analyzed statistically. The IC readings were obtained from the metabolic cart E-COVX ModuleTM. Results: The baseline demographics, APACHE-II, NUTRIC score, and SOFA scores on day 1, 3, and 7 were comparable between the two groups. The resting energy expenditure (REE) obtained in the IC group was significantly less than the WBE energy targets and the former were fed with significantly less calories. A significantly less percent reduction of QMT in the IC group compared with the WBE group was observed from day 1 to day 3, day 3 to day 7, and day 1 to day 7. Conclusion: From our study, we conclude that IC-REE-based nutrition is associated with lesser reduction in QMT and lesser calories fed in critically ill mechanically ventilated patients compared from WBE. CTRI registration-CTRI/2023/01/049119. How to cite this article: Chandrasekaran A, Pal D, Harne R, Patel SJ, Jagadeesh KN, Pachisia AV, et al. Comparison between Effect of Indirect Calorimetry vs Weight-based Equation (25 kcal/kg/day)-guided Nutrition on Quadriceps Muscle Thickness as Assessed by Bedside Ultrasonography in Medical Intensive Care Unit Patients: A Randomized Clinical Trial. Indian J Crit Care Med 2024;28(6):587-594.
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Sepsis is a life-threatening inflammatory response to infection, often accompanied by skeletal muscle atrophy. A previous study demonstrated that the administration of microRNA-140 (miR-140) attenuated lipopolysaccharide (LPS)-induced muscle atrophy, whereas miR-140 knockdown with siRNA promoted atrophy. Therefore, we investigated whether miR-140 is involved in LPS-induced muscle atrophy using a genetic model, miR-140-/- mice. We found that a single injection of LPS induced atrophy both in slow-twitch and fast-twitch muscles. The muscle weights and fiber cross-sectional areas were significantly reduced in both the wild-type (WT) and miR-140-/- mice, with no difference between genotypes. The expression of several proteolysis markers, muscle-specific RING-finger 1 (MuRF1) and MAFbx/atrogin-1, increased in both groups after LPS injection. The ubiquitinated proteins in the miR-140-/- mice were similar to those in the WT mice. Therefore, the deletion of miR-140 did not affect LPS-induced muscle atrophy.NEW & NOTEWORTHY We used miR-140-/- mice to determine the function of miR-140 in LPS-induced skeletal muscle atrophy. To our knowledge, this study is the first to examine slow-twitch muscles in LPS-induced muscle wasting after miR-140 manipulation.
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MicroARNs , Sepsis , Animales , Ratones , Lipopolisacáridos , MicroARNs/genética , MicroARNs/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Sepsis/complicaciones , Sepsis/genética , Sepsis/metabolismoRESUMEN
Cancer cachexia is common in many cancers and the loss of skeletal muscle mass compromises the response to therapies and quality of life. A contributing mechanism is oxidative stress and compounds able to attenuate it may be protective. Sulforaphane (SFN), a natural antioxidant in cruciferous vegetables, activates nuclear factor erythroid 2-related factor 2 (Nrf2) signaling to decrease oxidative stress. Although SFN has potential as a cancer therapeutic, whether it can attenuate muscle wasting in the absence or presence of chemotherapy is unknown. In healthy C2C12 myotubes, SFN administration for 48 h induced hypertrophy through increased myoblast fusion via Nrf2 and ERK signaling. To determine whether SFN could attenuate wasting induced by cancer cells, myotubes were cocultured with or without Colon-26 (C-26) cancer cells for 48 h and treated with 5-fluorouracil (5-FU, 5 µM) or vehicle (DMSO). SFN (10 µM) or DMSO was added for the final 24 h. Coculture with cancer cells in the absence and presence of 5-FU reduced myotube width by â¼30% (P < 0.001) and â¼20% (P < 0.01), respectively, which was attenuated by SFN (P < 0.05). Exposure to C-26 conditioned media reduced myotube width by 15% (P < 0.001), which was attenuated by SFN. Western immunoblotting and qRT-PCR confirmed activation of Nrf2 signaling and antioxidant genes. Coadministration of Nrf2 inhibitors (ML-385) or MEK inhibitors (PD184352) revealed that SFN's attenuation of atrophy was blocked by ERK inhibition. These data support the chemoprotective and antioxidative function of SFN in myotubes, highlighting its therapeutic potential for cancer-related muscle wasting.
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Antioxidantes , Neoplasias , Humanos , Antioxidantes/farmacología , Antioxidantes/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Dimetilsulfóxido/metabolismo , Calidad de Vida , Fibras Musculares Esqueléticas/metabolismo , Estrés Oxidativo , Atrofia Muscular/patología , Neoplasias/metabolismo , Fluorouracilo/farmacologíaRESUMEN
Immobilization leads to muscle wasting and insulin resistance, particularly during ageing. It has been suggested that undercarboxylated osteocalcin (ucOC) improves muscle mass and glucose metabolism. Bisphosphonates, an anti-osteoporosis treatment, might protect muscle wasting independent of ucOC. We hypothesize that the combination of ucOC and ibandronate (IBN) treatments has superior protective effects against immobilization-induced muscle wasting and insulin resistance than either treatment alone. C57BL/6J mice were hindlimb-immobilized for two weeks, with injections of vehicle, ucOC (90 ng/g daily) and/or IBN (2 µg/g weekly). Insulin/oral glucose tolerance tests (ITT/OGTT) were performed. Immediately after immobilization, muscles (extensor digitorum longus (EDL), soleus, tibialis anterior, gastrocnemius and quadriceps) were isolated and measured for muscle mass. Insulin-stimulated glucose uptake (EDL and soleus) was examined. Phosphorylation/expression of proteins in anabolic/catabolic pathways were examined in quadriceps. Primary human myotubes derived from older adult muscle biopsies were treated with ucOC and/or IBN, then signalling proteins were analysed. Combined treatment, but not individual treatments, significantly increased the muscle weight/body weight ratio in immobilized soleus (31.7%; P = 0.013) and quadriceps (20.0%; P = 0.0008) muscles, concomitant with elevated p-Akt (S473)/Akt ratio (P = 0.0047). Combined treatment also enhanced whole-body glucose tolerance (16.6%; P = 0.0011). In human myotubes, combined treatment stimulated greater activation of ERK1/2 (P = 0.0067 and 0.0072) and mTOR (P = 0.036), and led to a lesser expression of Fbx32 (P = 0.049) and MuRF1 (P = 0.048) than individual treatments. These findings suggest a potential therapeutic role for the ucOC and bisphosphonates combination in protecting against muscle wasting induced by immobilization and ageing. KEY POINTS: It has been suggested that undercarboxylated osteocalcin (ucOC) improves muscle mass and glucose metabolism. Bisphosphonates, an anti-osteoporosis treatment, might protect against muscle wasting independent of ucOC. The combination treatment of ucOC and ibandronate was shown to exert a greater therapeutic effect against immobilization-induced muscle wasting, and led to greater activation of anabolic pathway and less expression of catabolic signalling proteins in myotubes derived from older adults, compared with individual treatments. The combination treatment was found to improve whole-body glucose tolerance. Our findings suggest a potential therapeutic role for the ucOC and bisphosphonates combination in protecting against muscle wasting induced by immobilization and ageing.
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Resistencia a la Insulina , Animales , Ratones , Humanos , Anciano , Osteocalcina/metabolismo , Osteocalcina/farmacología , Ácido Ibandrónico/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Suspensión Trasera , Ratones Endogámicos C57BL , Atrofia Muscular/tratamiento farmacológico , Atrofia Muscular/etiología , Atrofia Muscular/prevención & control , Músculo Esquelético/metabolismo , Insulina/metabolismo , Glucosa/metabolismoRESUMEN
BACKGROUND & AIMS: Rapid deconditioning, also called cachexia, and metabolic reprogramming are two hallmarks of pancreatic cancer. Acetyl-coenzyme A synthetase short-chain family member 2 (ACSS2) is an acetyl-enzyme A synthetase that contributes to lipid synthesis and epigenetic reprogramming. However, the role of ACSS2 on the nonselective macropinocytosis and cancer cachexia in pancreatic cancer remains elusive. In this study, we demonstrate that ACSS2 potentiates macropinocytosis and muscle wasting through metabolic reprogramming in pancreatic cancer. METHODS: Clinical significance of ACSS2 was analyzed using samples from patients with pancreatic cancer. ACSS2-knockout cells were established using the clustered regularly interspaced short palindromic repeats-associated protein 9 system. Single-cell RNA sequencing data from genetically engineered mouse models was analyzed. The macropinocytotic index was evaluated by dextran uptake assay. Chromatin immunoprecipitation assay was performed to validate transcriptional activation. ACSS2-mediated tumor progression and muscle wasting were examined in orthotopic xenograft models. RESULTS: Metabolic stress induced ACSS2 expression, which is associated with worse prognosis in pancreatic cancer. ACSS2 knockout significantly suppressed cell proliferation in 2-dimensional and 3-dimensional models. Macropinocytosis-associated genes are upregulated in tumor tissues and are correlated with worse prognosis. ACSS2 knockout inhibited macropinocytosis. We identified Zrt- and Irt-like protein 4 (ZIP4) as a downstream target of ACSS2, and knockdown of ZIP4 reversed ACSS2-induced macropinocytosis. ACSS2 upregulated ZIP4 through ETV4-mediated transcriptional activation. ZIP4 induces macropinocytosis through cyclic adenosine monophosphate response element-binding protein-activated syndecan 1 (SDC1) and dynamin 2 (DNM2). Meanwhile, ZIP4 drives muscle wasting and cachexia via glycogen synthase kinase-ß (GSK3ß)-mediated secretion of tumor necrosis factor superfamily member 10 (TRAIL or TNFSF10). ACSS2 knockout attenuated muscle wasting and extended survival in orthotopic mouse models. CONCLUSIONS: ACSS2-mediated metabolic reprogramming activates the ZIP4 pathway, and promotes macropinocytosis via SDC1/DNM2 and drives muscle wasting through the GSK3ß/TRAIL axis, which potentially provides additional nutrients for macropinocytosis in pancreatic cancer.
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Acetato CoA Ligasa , Caquexia , Neoplasias Pancreáticas , Animales , Humanos , Ratones , Acetato CoA Ligasa/genética , Acetato CoA Ligasa/metabolismo , Adenosina Monofosfato , Caquexia/genética , Línea Celular Tumoral , Dextranos , Dinamina II , Glucógeno Sintasa Quinasa 3 beta , Lípidos , Músculos/metabolismo , Músculos/patología , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Sindecano-1 , Factores de Necrosis Tumoral , Neoplasias PancreáticasRESUMEN
Acute kidney injury (AKI) and intensive care unit-acquired weakness (ICU-AW) are 2 frequent complications of critical illness that, until recently, have been considered unrelated processes. The adverse impact of AKI on ICU mortality is clear, but its relationship with muscle weakness-a major source of ICU morbidity-has not been fully elucidated. Furthermore, improving ICU survival rates have refocused the field of intensive care toward improving long-term functional outcomes of ICU survivors. We begin our review with the epidemiology of AKI in the ICU and of ICU-AW, highlighting emerging data suggesting that AKI and AKI treated with kidney replacement therapy (AKI-KRT) may independently contribute to the development of ICU-AW. We then delve into human and animal data exploring the pathophysiologic mechanisms linking AKI and acute KRT to muscle wasting, including altered amino acid and protein metabolism, inflammatory signaling, and deleterious removal of micronutrients by KRT. We next discuss the currently available interventions that may mitigate the risk of ICU-AW in patients with AKI and AKI-KRT. We conclude that additional studies are needed to better characterize the epidemiologic and pathophysiologic relationship between AKI, AKI-KRT, and ICU-AW and to prospectively test interventions to improve the long-term functional status and quality of life of AKI survivors.
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Lesión Renal Aguda , Calidad de Vida , Humanos , Unidades de Cuidados Intensivos , Cuidados Críticos , Terapia de Reemplazo Renal/efectos adversos , Lesión Renal Aguda/terapia , Enfermedad CríticaRESUMEN
INTRODUCTION/AIMS: Individuals with dysferlinopathies, a group of genetic muscle diseases, experience delay in the onset of muscle weakness. The cause of this delay and subsequent muscle wasting are unknown, and there are currently no clinical interventions to limit or prevent muscle weakness. To better understand molecular drivers of dysferlinopathies, age-dependent changes in the proteomic profile of skeletal muscle (SM) in wild-type (WT) and dysferlin-deficient mice were identified. METHODS: Quadriceps were isolated from 6-, 18-, 42-, and 77-wk-old C57BL/6 (WT, Dysf+/+ ) and BLAJ (Dysf-/- ) mice (n = 3, 2 male/1 female or 1 male/2 female, 24 total). Whole-muscle proteomes were characterized using liquid chromatography-mass spectrometry with relative quantification using TMT10plex isobaric labeling. Principle component analysis was utilized to detect age-dependent proteomic differences over the lifespan of, and between, WT and dysferlin-deficient SM. The biological relevance of proteins with significant variation was established using Ingenuity Pathway Analysis. RESULTS: Over 3200 proteins were identified between 6-, 18-, 42-, and 77-wk-old mice. In total, 46 proteins varied in aging WT SM (p < .01), while 365 varied in dysferlin-deficient SM. However, 569 proteins varied between aged-matched WT and dysferlin-deficient SM. Proteins with significant variation in expression across all comparisons followed distinct temporal trends. DISCUSSION: Proteins involved in sarcolemma repair and regeneration underwent significant changes in SM over the lifespan of WT mice, while those associated with immune infiltration and inflammation were overly represented over the lifespan of dysferlin-deficient mice. The proteins identified herein are likely to contribute to our overall understanding of SM aging and dysferlinopathy disease progression.
RESUMEN
Stroke cachexia is associated with prolonged inflammation, muscle loss, poor prognosis, and early death of stroke patients. No particular treatment is available to cure the symptoms or disease. The present study aimed to evaluate the effect of a 5-HT1a agonist, buspirone on stroke cachexia. Wistar rats were injected with endothelin-1 to the bregma region of the brain to induce ischemic stroke followed by induction of cachexia after 4 days. Treatment with buspirone (3 mg/kg p.o) was given for 4 weeks after confirmation of cachexia in animals. Disease control animals exhibited decrease in wire hanging time and increase in foot fault numbers compared to normal animals. Disease control animals also showed weight loss, decrease in food intake, increased serum glucose and lipid profile along with high serum levels of inflammatory cytokines-TNF-α, IL-6 and decrease in weight of skeletal muscle and adipose tissues. Treatment with buspirone improves behavioural parameters along with increases food intake and body weight, decreased inflammatory cytokines IL-6 and TNF-α and serum glucose levels with increase in lipid profile. Buspirone also increased the weight of adipose tissue and maintain the skeletal muscle architecture and function as depicted in histopathological studies. Our study suggests that buspirone produces beneficial role in stroke cachexia by increasing body weight, food intake and adipose tissue depots by activating on 5-HT receptors. Buspirone decreases inflammatory markers in stroke cachexia although mechanism behind it was not fully understood. Buspirone decreases circulating blood glucose by stimulating glucose uptake in skeletal muscle via 5-HT receptors and maintained lipid profile. Buspirone was found to be effective in ameliorating cachectic conditions in stroke.
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Caquexia , Accidente Cerebrovascular , Ratas , Animales , Caquexia/tratamiento farmacológico , Caquexia/etiología , Factor de Necrosis Tumoral alfa/farmacología , Endotelina-1 , Buspirona/farmacología , Interleucina-6 , Ratas Wistar , Citocinas/farmacología , Músculo Esquelético/patología , Lípidos , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/patología , Glucosa/farmacologíaRESUMEN
BACKGROUND: Critically ill patients suffer from acute muscle wasting, which is associated with significant physical functional impairment. We describe data from nested muscle biopsy studies from two trials of functional electrical stimulation (FES) that did not shown improvements in physical function. METHODS: Primary cohort: single-centre randomized controlled trial. Additional healthy volunteer data from patients undergoing elective hip arthroplasty. Validation cohort: Four-centre randomized controlled trial. INTERVENTION: FES cycling for 60-90min/day. ANALYSES: Skeletal muscle mRNA expression of 223 genes underwent hierarchal clustering for targeted analysis and validation. RESULTS: Positively enriched pathways between healthy volunteers and ICU participants were "stress response", "response to stimuli" and "protein metabolism", in keeping with published data. Positively enriched pathways between admission and day 7 ICU participants were "FOXO-mediated transcription" (admission = 0.48 ± 0.94, day 7 = - 0.47 ± 1.04 mean log2 fold change; P = 0.042), "Fatty acid metabolism" (admission = 0.50 ± 0.67, day 7 = 0.07 ± 1.65 mean log2 fold change; P = 0.042) and "Interleukin-1 processing" (admission = 0.88 ± 0.50, day 7 = 0.97 ± 0.76 mean log2 fold change; P = 0.054). Muscle mRNA expression of UCP3 (P = 0.030) and DGKD (P = 0.040) decreased in both cohorts with no between group differences. Changes in IL-18 were not observed in the validation cohort (P = 0.268). Targeted analyses related to intramuscular mitochondrial substrate oxidation, fatty acid oxidation and intramuscular inflammation showed PPARγ-C1α; (P < 0.001), SLC25A20 (P = 0.017) and UCP3 (P < 0.001) decreased between admission and day 7 in both arms. LPIN-1 (P < 0.001) and SPT1 (P = 0.044) decreased between admission and day 7. IL-18 (P = 0.011) and TNFRSF12A (P = 0.009) increased in both arms between admission and day 7. IL-1ß (P = 0.007), its receptor IL-1R1 (P = 0.005) and IL-6R (P = 0.001) decreased in both arms between admission and day 7. No between group differences were seen in any of these (all p > 0.05). CONCLUSIONS: Intramuscular inflammation and altered substrate utilization are persistent in skeletal muscle during first week of critical illness and are not improved by the application of Functional Electrical Stimulation-assisted exercise. Future trials of exercise to prevent muscle wasting and physical impairment are unlikely to be successful unless these processes are addressed by other means than exercise alone.