Year: 2011
Type: article
Abstract: Cancer cachexia is a syndrome characterized by severe wasting of adipose tissue and skeletal muscle caused partly by chronic, systemic inflammation.Conjugated linoleic acids (CLA) are a group of dietary fatty acids that have been reported to have antiinflammatory properties, which are mainly attributed to the cis-9, trans-11 (c9t11-) CLA isomer.The first objective of this research was to determine whether a c9t11-CLA-rich oil (6:1 c9t11: t10c12) could attenuate skeletal muscle wasting and adipose atrophy in a mouse model of cancer cachexia, male CD2F1 mice inoculated with 1×10 6 colon-26 adenocarcinoma (C26) cells.In this study, the loss of body weight, muscle and adipose tissue mass caused by tumors were not rescued by supplementation with 1% of the c9t11-CLA-rich oil.In quadriceps muscle, c9t11-CLA-rich oil exacerbated tumor-induced gene expression of inflammatory markers tumor necrosis factor alpha (TNFα), interleukin (IL)-6 receptor and the E3 ligase muscle ring finger -1 (MuRF-1) involved in muscle proteolysis.In epididymal adipose tissue, tumor-driven delipidation and atrophy was aggravated by the c9,t11-CLA-rich oil, demonstrated by further reduced adipocyte size and lower adiponectin expression.These data suggest that addition of c9t11-CLA-rich oil (0.6% c9t11, 0.1% t10c12) in diet did not ameliorate iii wasting in mice with cancer cachexia.Instead, it increased expression of inflammatory markers in the muscle and increased adipose delipidation.The second objective was to understand whether cardiac muscle is adversely affected in cancer cachexia.Alterations in cardiac muscle metabolism have been observed in tumor-bearing animals and cancer patients in earlier research, but it remains unclear whether cancer cachexia causes heart failure.We investigated the effect of cancer cachexia on heart contractile function and cardiac muscle structure in the same mouse model.Heart contractile function was measured by echocardiography in vivo on day 14 after tumor inoculation, and all mice were sacrificed on day 17 for other analysis.Mice from Tumor group had an impaired heart contractile function compared to mice from No Tumor group.In hearts of Tumor mice compared to No Tumor group, there was marked fibrosis demonstrated by Masson's trichrome staining and transmission electron microscopy revealed disrupted myocardial ultrastructure.Gene expression of the regulator of cardiac muscle contraction troponin I was significantly reduced.Moreover, both mRNA and protein levels of myosin heavy chain (MHC) were altered whereby MHCα (adult isoform) was decreased and MHCβ (fetal isoform) was increased indicating reactivation of the fetal gene expression pattern.These data suggest that heart function was diminished in mice with cancer cachexia, and this impaired function was associated with increased fibrosis, disrupted myocardial structure and altered composition of contractile proteins of cardiac muscle.iv The third objective of the research was to further characterize this mouse model to investigate the possible underlying mechanisms for decreased heart function.In cachectic mice bearing C26 tumors compared to mice without tumors, there was an induced gene expression pattern for cardiac remodeling, including increased BNP, c-fos, decreased PPARα and its responsive gene CPT1β, and a switch from "adult" isoforms (MHCα, GLUT4) to "fetal" isoforms (MHCβ, GLUT1).Echocardiography identified a decreased cardiac wall thickness.RT-PCR and western blotting revealed a decreased amount of the major cardiac myofibrillar proteins MHC and troponin I, induced expression of atrogenes (MuRF-1 and Atrogin-1), and increased amount of ubiquitinated proteins.These data provide evidence for cardiac muscle atrophy through the ubiquitin-proteasome mediated proteolysis in mice with cancer cachexia.Regulatory signaling pathways might involve p44/42 MAPK and need to be confirmed in future research.v Dedicated to my mom.
Author: Min Tian
Institution: The Ohio State University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2599017653