A novel myokine, secreted protein acidic and rich in cysteine (SPARC), suppresses colon tumorigenesis via regular exercise
- Wataru Aoi1,
- Yuji Naito2,
- Tomohisa Takagi2,
- Yuko Tanimura2,
- Yoshikazu Takanami3,
- Yukari Kawai4,
- Kunihiro Sakuma5,
- Liu Po Hang2,
- Katsura Mizushima2,
- Yasuko Hirai2,
- Ryota Koyama2,
- Sayori Wada1,
- Akane Higashi1,
- Satoshi Kokura2,
- Hiroshi Ichikawa6,
- Toshikazu Yoshikawa2
- 1Laboratory of Health Science, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto, Japan
- 2Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
- 3Department of Home Economics, Otsuma Women's University, Tokyo, Japan
- 4Louis Pasteur Center for Medical Research, Kyoto, Japan
- 5Health Science Center, Toyohashi University of Technology, Toyohashi, Japan
- 6Department of Medical Life Systems, Doshisha University, Kyotanabe, Japan
- Correspondence to Dr Wataru Aoi, Laboratory of Health Science, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, 1-5 Hangi-cho Shimogamo, Sakyo-ku, Kyoto 606-8522, Japan;
Contributors WA designed the study, performed most of the experiments, analysed the data and wrote the manuscript; YN, TT and SK designed and performed experiments that involved the mouse tumour model; YT, YK, SW and AH helped perform the experiments evaluating with human samples; YT, LPH and RK assisted with the mouse and culture experiments; KS and YH performed the immunohistochemical analysis; KM conducted the transcriptome analysis; YN and HI designed the study and evaluated the data; TY supervised the overall project.
- Revised 16 June 2012
- Accepted 3 July 2012
- Published Online First 31 July 2012
Objective Several epidemiological studies have shown that regular exercise can prevent the onset of colon cancer, although the underlying mechanism is unclear. Myokines are secreted skeletal muscle proteins responsible for some exercise-induced health benefits including metabolic improvement and anti-inflammatory effects in organs. The purpose of this study was to identify new myokines that contribute to the prevention of colon tumorigenesis.
Methods To identify novel secreted muscle-derived proteins, DNA microarrays were used to compare the transcriptome of muscle tissue in sedentary and exercised young and old mice. The level of circulating secreted protein acidic and rich in cysteine (SPARC) was measured in mice and humans that performed a single bout of exercise. The effect of SPARC on colon tumorigenesis was examined using SPARC-null mice. The secretion and function of SPARC was examined in culture experiments.
Results A single bout of exercise increased the expression and secretion of SPARC in skeletal muscle in both mice and humans. In addition, in an azoxymethane-induced colon cancer mouse model, regular low-intensity exercise significantly reduced the formation of aberrant crypt foci in wild-type mice but not in SPARC-null mice. Furthermore, regular exercise enhanced apoptosis in colon mucosal cells and increased the cleaved forms of caspase-3 and caspase-8 in wild-type mice but not in SPARC-null mice. Culture experiments showed that SPARC secretion from myocytes was induced by cyclic stretch and inhibited proliferation with apoptotic effect of colon cancer cells.
Conclusions These findings suggest that exercise stimulates SPARC secretion from muscle tissues and that SPARC inhibits colon tumorigenesis by increasing apoptosis.
- Skeletal muscle
- colon cancer
- colorectal physiology
- colorectal cancer
- oxidative stress
- inflammatory bowel disease
- inflammatory mediators
- ibd models
- gastric inflammation
- amino acids
- cell biology
- amino acids
- mucosal repair
- oxidative stress
Funding This work was supported by Grants-in-Aid from the Japan Society for the Promotion of Science (23700776WA, 08101559YN and 21390184TY) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and research grants from the Adaptable and Seamless Technology Transfer Program through Target Driven R&D from the Japan Science and Technology Agency, Kyoto Prefectural University Corporation, Nakatomi Foundation and Uehara Memorial Foundation.
Correction notice This article has been corrected since it was published Online First. The following sentence has been amended to read: SPARC demonstrated accelerated cell proliferation compared with medium obtained from normal muscle cells (figure 5C).
Competing interests None.
Patient consent Obtained.
Ethics approval The experimental protocol was approved by the Review Board on Human Experiments, Kyoto Prefectural University and complied with the Helsinki Declaration.
Provenance and peer review Not commissioned; externally peer reviewed.