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

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.

SUBMITTER: de Castro GS

PROVIDER: S-EPMC6770124 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

de Castro Gabriela S GS Simoes Estefania E Lima Joanna D C C JDCC Ortiz-Silva Milene M Festuccia William T WT Tokeshi Flávio F Alcântara Paulo S PS Otoch José P JP Coletti Dario D Seelaender Marilia M

Cancers 20190828 9

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 ...[more]

PMID: 31466311

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Project description:BackgroundSkeletal muscle wasting is a devastating consequence of cancer that affects up to 80% of cancer patients and associates with reduced survival. Herein, we investigated the biological significance of Forkhead box P1 (FoxP1), a transcriptional repressor that we demonstrate is up-regulated in skeletal muscle in multiple models of cancer cachexia and in cachectic cancer patients.MethodsInducible, skeletal muscle-specific FoxP1 over-expressing (FoxP1iSkmTg/Tg ) mice were generated through crossing conditional Foxp1a transgenic mice with HSA-MCM mice that express tamoxifen-inducible Cre recombinase under control of the skeletal muscle actin promoter. To determine the requirement of FoxP1 for cancer-induced skeletal muscle wasting, FoxP1-shRNA was packaged and targeted to muscles using AAV9 delivery prior to inoculation of mice with Colon-26 Adenocarcinoma (C26) cells.ResultsUp-regulation of FoxP1 in adult skeletal muscle was sufficient to induce features of cachexia, including 15% reduction in body mass (P < 0.05), and a 16-27% reduction in skeletal muscle mass (P < 0.05) that was characterized by a 20% reduction in muscle fibre cross-sectional area of type IIX/B muscle fibres (P = 0.020). Skeletal muscles from FoxP1iSkmTg/Tg mice also showed significant damage and myopathy characterized by the presence of centrally nucleated myofibres, extracellular matrix expansion, and were 19-26% weaker than controls (P < 0.05). Transcriptomic analysis revealed FoxP1 as a potent transcriptional repressor of skeletal muscle gene expression, with enrichment of pathways related to skeletal muscle structure and function, growth signalling, and cell quality control. Because FoxP1 functions, at least in part, as a transcriptional repressor through its interaction with histone deacetylase proteins, we treated FoxP1iSkmTg/Tg mice with Trichostatin A, and found that this completely prevented the loss of muscle mass (p = 0.007) and fibre atrophy (P < 0.001) in the tibialis anterior. In the context of cancer, FoxP1 knockdown blocked the cancer-induced repression of myocyte enhancer factor 2 (MEF2)-target genes critical to muscle differentiation and repair, improved muscle ultrastructure, and attenuated muscle fibre atrophy by 50% (P < 0.05).ConclusionsIn summary, we identify FoxP1 as a novel repressor of skeletal muscle gene expression that is increased in cancer cachexia, whose up-regulation is sufficient to induce skeletal muscle wasting and weakness, and required for the normal wasting response to cancer.

Project description:BACKGROUND: Cancer cachexia is a multi-organ tissue wasting syndrome that contributes to morbidity and mortality in many cancer patients. Skeletal muscle loss represents an established key feature yet there is no molecular understanding of the disease process. In fact, the postulated molecular regulators of cancer cachexia originate largely from pre-clinical models and it is unclear how these translate to the clinical environment. METHODS: Rectus abdominis muscle biopsies were obtained from 65 upper gastrointestinal (UGI) cancer patients during open surgery and RNA profiling was performed on a subset of this cohort (n = 21) using the Affymetrix U133+2 platform. Quantitative analysis revealed a gene signature, which underwent technical validation and independent confirmation in a separate clinical cohort. RESULTS: Quantitative significance analysis of microarrays produced an 83-gene signature that was able to identify patients with greater than 5% weight loss, while this molecular profile was unrelated to markers of systemic inflammation. Selected genes correlating with weight loss were validated using quantitative real-time PCR and independently studied as general cachexia biomarkers in diaphragm and vastus lateralis from a second cohort (n = 13; UGI cancer patients). CaMKIIbeta correlated positively with weight loss in all muscle groups and CaMKII protein levels were elevated in rectus abdominis. TIE1 was also positively associated with weight loss in both rectus abdominis and vastus lateralis muscle groups while other biomarkers demonstrated tissue-specific expression patterns. Candidates selected from the pre-clinical literature, including FOXO protein and ubiquitin E3 ligases, were not related to weight loss in this human clinical study. Furthermore, promoter analysis identified that the 83 weight loss-associated genes had fewer FOXO binding sites than expected by chance. CONCLUSION: We were able to discover and validate new molecular biomarkers of human cancer cachexia. The exercise activated genes CaMKIIbeta and TIE1 related positively to weight-loss across muscle groups, indicating that this cachexia signature is not simply due to patient inactivity. Indeed, excessive CaMKIIbeta activation is a potential mechanism for reduced muscle protein synthesis. Our genomics analysis also supports the view that the available preclinical models do not accurately reflect the molecular characteristics of human muscle from cancer cachexia patients.

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

Publications

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

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