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

Author(s)

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]}

Affiliation

^[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

• Document type: Journal article
• Source: CANCERS; v. 11, n. 9 SEP 2019.
• Web of Science Citations: 0

Abstract

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)

• FAPESP's process: 16/02780-1 - Molecular analysis in the tumor microenvironment of cachectic patients: A search of markers for early diagnosis of the syndrome
• Grantee: Joanna Darck Carola Correia Lima
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 12/50079-0 - Systemic inflammation in cachectic cancer patients: mechanisms and therapeutical strategies, a translational medicine approach
• Grantee: Marilia Cerqueira Leite Seelaender
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 16/13810-9 - Cachexia associated with cancer and lipid metabolism: can chronic exercise affect fatty acids location and profile in muscle?
• Grantee: Gabriela Salim Ferreira de Castro
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/12508-7 - Hypothalamic changes related to the syndrome of cachexia associated with cancer: morphological analysis and histological, molecular, cellular and systemic central nervous system study
• Grantee: Estefania Simoes Fernandez
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 17/12260-8 - Autophagy involvement in the metabolic and inflammatory alterations in adipose tissue associated with Obesity induced by high fat diet
• Grantee: Milene Ortiz Silva
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)