Human Cachexia Induces Changes in Mitochondria, Autophagy and Apoptosis in the Skeletal Muscle

Autor(es)

de Castro, Gabriela S. ^[1] ; Simoes, Estefania ^[1] ; Lima, Joanna D. C. C. ^[1] ; Ortiz-Silva, Milene ^[2] ; Festuccia, William T. ^[2] ; Tokeshi, Flivio ^[3] ; Alcantara, Paulo S. ^[3] ; Otoch, Jose P. ^[3] ; Coletti, Dario ^[4] ; Seelaender, Marilia ^{[3, 1]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Cell & Tissue Biol, Canc Metab Res Grp, BR-05508900 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, BR-05508900 Sao Paulo - Brazil

^[3] Univ Sao Paulo, Fac Med, Dept Clin Surg, BR-01246903 Sao Paulo - Brazil

^[4] Sorbonne Univ, Dept Biol Adaptat & Aging, B2A, CNRS UMR 8256, INSERM ERL U1164, UPMC P6, F-75005 Paris - France

• Tipo de documento: Artigo Científico
• Fonte: CANCERS; v. 11, n. 9 SEP 2019.
• Citações Web of Science: 0

Resumo

Cachexia is a wasting syndrome characterized by the continuous loss of skeletal muscle mass due to imbalance between protein synthesis and degradation, which is related with poor prognosis and compromised quality of life. Dysfunctional mitochondria are associated with lower muscle strength and muscle atrophy in cancer patients, yet poorly described in human cachexia. We herein investigated mitochondrial morphology, autophagy and apoptosis in the skeletal muscle of patients with gastrointestinal cancer-associated cachexia (CC), as compared with a weight-stable cancer group (WSC). CC showed prominent weight loss and increased circulating levels of serum C-reactive protein, lower body mass index and decreased circulating hemoglobin, when compared to WSC. Electron microscopy analysis revealed an increase in intermyofibrillar mitochondrial area in CC, as compared to WSC. Relative gene expression of Fission 1, a protein related to mitochondrial fission, was increased in CC, as compared to WSC. LC3 II, autophagy-related (ATG) 5 and 7 essential proteins for autophagosome formation, presented higher content in the cachectic group. Protein levels of phosphorylated p53 (Ser46), activated caspase 8 (Asp384) and 9 (Asp315) were also increased in the skeletal muscle of CC. Overall, our results demonstrate that human cancer-associated cachexia leads to exacerbated muscle-stress response that may culminate in muscle loss, which is in part due to disruption of mitochondrial morphology, dysfunctional autophagy and increased apoptosis. To the best of our knowledge, this is the first report showing quantitative morphological alterations in skeletal muscle mitochondria in cachectic patients. (AU)

• Processo FAPESP: 16/02780-1 - Análise molecular no microambiente tumoral de pacientes caquéticos: Uma busca de marcadores para diagnóstico precoce da síndrome.
• Beneficiário: Joanna Darck Carola Correia Lima
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 19/08682-0 - Caquexia induz alterações na mitocôndria, autofagia e apoptose em músculo esquelético de pacientes com câncer.
• Beneficiário: Marilia Cerqueira Leite Seelaender
• Modalidade de apoio: Auxílio à Pesquisa - Publicações científicas - Artigo
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• Processo FAPESP: 16/12508-7 - Alterações hipotalâmicas relacionadas com a síndrome da caquexia associada ao câncer: análise morfológica e estudo histológico, molecular, celular e sistêmico do sistema nervoso central
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• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
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• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto