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1.
EMBO Rep ; 2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39251827

RESUMO

The fat body in Drosophila larvae functions as a reserve tissue and participates in the regulation of organismal growth and homeostasis through its endocrine activity. To better understand its role in growth coordination, we induced fat body atrophy by knocking down several key enzymes of the glycolytic pathway in adipose cells. Our results show that impairing the last steps of glycolysis leads to a drastic drop in adipose cell size and lipid droplet content, and downregulation of the mTOR pathway and REPTOR transcriptional activity. Strikingly, fat body atrophy results in the distant disorganization of body wall muscles and the release of muscle-specific proteins in the hemolymph. Furthermore, we showed that REPTOR activity is required for fat body atrophy downstream of glycolysis inhibition, and that the effect of fat body atrophy on muscles depends on the production of TNF-α/egr and of the insulin pathway inhibitor ImpL2.

2.
Proc Natl Acad Sci U S A ; 120(34): e2215095120, 2023 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-37585460

RESUMO

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.


Assuntos
Neoplasias Pancreáticas , Fator de Crescimento Transformador beta , Humanos , Camundongos , Animais , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Caquexia/genética , Atrofia Muscular/genética , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Músculo Esquelético/metabolismo , Fatores de Transcrição de Resposta de Crescimento Precoce/genética , Fatores de Transcrição de Resposta de Crescimento Precoce/metabolismo
3.
Am J Physiol Cell Physiol ; 327(3): C684-C697, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39010842

RESUMO

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.


Assuntos
Caquexia , Carcinoma Pulmonar de Lewis , Gotículas Lipídicas , Camundongos Endogâmicos C57BL , Músculo Esquelético , Animais , Caquexia/metabolismo , Caquexia/patologia , Caquexia/etiologia , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patologia , Carcinoma Pulmonar de Lewis/complicações , Gotículas Lipídicas/metabolismo , Gotículas Lipídicas/patologia , Camundongos , Metabolismo dos Lipídeos , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/patologia , Mitocôndrias Musculares/ultraestrutura , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Mitocôndrias/ultraestrutura
4.
Physiol Genomics ; 56(7): 483-491, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38738317

RESUMO

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.


Assuntos
COVID-19 , Desidratação , Metaboloma , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Desidratação/metabolismo , COVID-19/metabolismo , COVID-19/complicações , Idoso , Metabolômica/métodos , Respiração Artificial , Injúria Renal Aguda/metabolismo , Adulto , SARS-CoV-2 , Estudos de Coortes , Aminoácidos/metabolismo , Aminoácidos/sangue , Ureia/metabolismo , Ureia/sangue , Concentração Osmolar
5.
Apoptosis ; 29(5-6): 663-680, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38598070

RESUMO

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.


Assuntos
Caquexia , Proteína Forkhead Box O3 , Doenças Musculares , Neoplasias , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Síndrome de Emaciação , Caquexia/etiologia , Caquexia/metabolismo , Caquexia/terapia , Doenças Musculares/etiologia , Doenças Musculares/metabolismo , Doenças Musculares/terapia , Neoplasias/complicações , Redes e Vias Metabólicas , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Síndrome de Emaciação/etiologia , Síndrome de Emaciação/metabolismo , Síndrome de Emaciação/terapia , Animais , Modelos Animais de Doenças , Camundongos , Linhagem Celular , Masculino , Camundongos Endogâmicos BALB C , Perfilação da Expressão Gênica
6.
Biochem Biophys Res Commun ; 733: 150650, 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39255618

RESUMO

The widely used chemotherapeutic drug doxorubicin (DOX) has been associated with adverse effects on the skeletal muscle, which can persist for years after the end of the treatment. These adverse effects may be exacerbated in older patients, whose skeletal muscle might already be impaired by aging. Nonetheless, the mediators responsible for DOX-induced myotoxicity are still largely unidentified, particularly the ones involved in the long-term effects that negatively affect the quality of life of the patients. Therefore, this study aimed to investigate the long-term effects of the chronic administration of DOX on the soleus muscle of aged mice. For that and to mimic the clinical regimen, a dose of 1.5 mg kg-1 of DOX was administered two times per week for three consecutive weeks in a cumulative dose of 9 mg kg-1 to 19-month-old male mice, which were sacrificed two months after the last administration. Body wasting and the atrophy of the soleus muscle, as measured by a decrease in the cross-sectional area of the soleus muscle fibers, were identified as long-term effects of DOX administration. The atrophy observed was correlated with increased reactive oxygen species production and caspase-3 activity. An impaired skeletal muscle regeneration was also suggested due to the correlation between satellite cells activation and the soleus muscle fibers atrophy. Systemic inflammation, skeletal muscle energy metabolism and neuromuscular junction-related markers do not appear to be involved in the long-term DOX-induced skeletal muscle atrophy. The data provided by this study shed light on the mediators involved in the overlooked long-term DOX-induced myotoxicity, paving the way to the improvement of the quality of life and survival rates of older cancer patients.

7.
J Transl Med ; 22(1): 506, 2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38802952

RESUMO

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.


Assuntos
Caquexia , Vesículas Extracelulares , Neoplasias , Humanos , Caquexia/metabolismo , Caquexia/etiologia , Caquexia/terapia , Vesículas Extracelulares/metabolismo , Neoplasias/complicações , Neoplasias/patologia , Neoplasias/metabolismo , Animais
8.
Eur J Clin Invest ; : e14288, 2024 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-39058257

RESUMO

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.

9.
Nutr Metab Cardiovasc Dis ; 34(3): 606-617, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38000999

RESUMO

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 ∼20 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.


Assuntos
Insuficiência Cardíaca , Sarcopenia , Deficiência de Vitamina D , Vitamina D/análogos & derivados , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Masculino , Sarcopenia/diagnóstico , Sarcopenia/epidemiologia , Sarcopenia/prevenção & controle
10.
BMC Anesthesiol ; 24(1): 308, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39237875

RESUMO

OBJECTIVES: Critically ill patients with severe pancreatitis exhibit substantial muscle wasting, which limits in-hospital and post-hospital outcomes. Survivors of critical illness undergo extensive recovery processes. Previous studies have explored pancreatic function, quality of life, and costs post-hospitalization for AP patients, but none have comprehensively quantified muscle loss and recovery post-discharge. By applying an AI-based automated segmentation tool, we aimed to quantify muscle mass recovery in ICU patients after discharge. MATERIALS: Muscle segmentation was performed on 22 patients, with a minimum of three measurements taken during hospitalization and one clinically indicated examination after hospital discharge. Changes in psoas muscle area (PMA) between admission, discharge and follow up were calculated. T-Test was performed to identify significant differences between patients able and not able to recover their muscle mass. RESULTS: Monitoring PMA shows muscle loss during and gain after hospitalization: The mean PMA at the first scan before or at ICU admission (TP1) was 17.08 cm², at the last scan before discharge (TP2), mean PMA was 9.61 cm². The percentage change in PMA between TP1 and TP2 ranged from - 85.42% to -2.89%, with a mean change of -40.18%. The maximum muscle decay observed during the stay was - 50.61%. After a mean follow-up period of 438.73 days most patients (81%) were able to increase their muscle mass. Compared to muscle status at TP1, only 27% of patients exhibited full recovery, with the majority still presenting a deficit of 31.96%. CONCLUSION: Muscle recovery in ICU patients suffering from severe AP is highly variable, with only about one third of patients recovering to their initial physical status. Opportunistic screening of post-ICU patient recovery using clinically indicated imaging and AI-based segmentation tools enables precise quantification of patients' muscle status and can be employed to identify individuals who fail to recover and would benefit from secondary rehabilitation. Understanding the dynamics of muscle atrophy may improve prognosis and support personalized patient care.


Assuntos
Unidades de Terapia Intensiva , Pancreatite , Músculos Psoas , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Longitudinais , Pancreatite/fisiopatologia , Músculos Psoas/diagnóstico por imagem , Idoso , Adulto , Recuperação de Função Fisiológica/fisiologia , Hospitalização/estatística & dados numéricos , Estado Terminal , Doença Aguda
11.
Neurocrit Care ; 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38918337

RESUMO

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.

12.
Int J Mol Sci ; 25(11)2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38891777

RESUMO

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.


Assuntos
Microbioma Gastrointestinal , Músculo Esquelético , Distrofia Muscular de Duchenne , Distrofia Muscular de Duchenne/microbiologia , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patologia , Humanos , Animais , Músculo Esquelético/metabolismo , Músculo Esquelético/microbiologia
13.
Int J Mol Sci ; 25(14)2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-39062775

RESUMO

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.


Assuntos
Neoplasias da Mama , Exercício Físico , Músculo Esquelético , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Feminino , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , Qualidade de Vida , Terapia por Exercício/métodos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo
14.
Aust Crit Care ; 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38834392

RESUMO

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.

15.
Indian J Crit Care Med ; 28(6): 587-594, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-39130394

RESUMO

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.

16.
Am J Physiol Cell Physiol ; 325(2): C509-C518, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37486067

RESUMO

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.


Assuntos
MicroRNAs , Sepse , Animais , Camundongos , Lipopolissacarídeos , MicroRNAs/genética , MicroRNAs/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Sepse/complicações , Sepse/genética , Sepse/metabolismo
17.
Am J Physiol Cell Physiol ; 324(2): C205-C221, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36534500

RESUMO

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 ∼30% (P < 0.001) and ∼20% (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.


Assuntos
Antioxidantes , Neoplasias , Humanos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Dimetil Sulfóxido/metabolismo , Qualidade de Vida , Fibras Musculares Esqueléticas/metabolismo , Estresse Oxidativo , Atrofia Muscular/patologia , Neoplasias/metabolismo , Fluoruracila/farmacologia
18.
J Physiol ; 601(10): 1851-1867, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36999349

RESUMO

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.


Assuntos
Resistência à Insulina , Animais , Camundongos , Humanos , Idoso , Osteocalcina/metabolismo , Osteocalcina/farmacologia , Ácido Ibandrônico/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Elevação dos Membros Posteriores , Camundongos Endogâmicos C57BL , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/etiologia , Atrofia Muscular/prevenção & controle , Músculo Esquelético/metabolismo , Insulina/metabolismo , Glucose/metabolismo
19.
Gastroenterology ; 163(5): 1281-1293.e1, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35777482

RESUMO

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.


Assuntos
Acetato-CoA Ligase , Caquexia , Neoplasias Pancreáticas , Animais , Humanos , Camundongos , Acetato-CoA Ligase/genética , Acetato-CoA Ligase/metabolismo , Monofosfato de Adenosina , Caquexia/genética , Linhagem Celular Tumoral , Dextranos , Dinamina II , Glicogênio Sintase Quinase 3 beta , Lipídeos , Músculos/metabolismo , Músculos/patologia , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Sindecana-1 , Fatores de Necrose Tumoral , Neoplasias Pancreáticas
20.
Am J Kidney Dis ; 81(3): 336-351, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36332719

RESUMO

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.


Assuntos
Injúria Renal Aguda , Qualidade de Vida , Humanos , Unidades de Terapia Intensiva , Cuidados Críticos , Terapia de Substituição Renal/efeitos adversos , Injúria Renal Aguda/terapia , Estado Terminal
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