Effects of Insulin-Like Growth Factor 1 on Muscle Atrophy and Motor Function in Rats with Brain Ischemia

10.4077/CJP.2010.AMK080

Heng-Chih Chang；Yea-Ru Yang；Paulus S. Wang；Chia-Hua Kuo；Ray-Yau Wang

insulin-like growth factor 1 ； muscle atrophy ； motor function ； brain ischemia

The Chinese Journal of Physiology

53卷5期（2010 / 10 / 31）

337 - 348

英文

Although insulin-like growth factor 1 (IGF 1) has been used in immobilizated muscles to prevent muscle atrophy, its effects on muscle atrophy after brain ischemia are not known. This study aimed to determine the effects of IGF 1 on preventing muscle atrophy in rats with brain ischemia. Middle cerebral artery occlusion (MCAO) was used to induce the brain ischemia. In the first part of the study, rats were assigned to sham control, ischemic control, and ischemia with different dosages of IGF 1 injection groups to determine the optimal dosage of IGF 1 on preventing muscle atrophy after brain ischemia. In the second part of the study, rats were assigned to sham control, ischemic control, ischemia with IGF 1, or with IGF 1 receptor inhibitor (AG1024) injection groups to determine the specificity of IGF 1 on preventing muscle atrophy after brain ischemia. IGF 1 or AG1024 was injected locally to calf muscles and anterior tibialis (TA) starting from one day after brain ischemia and injections were carried out every other day for 4 times. Muscle weight and myosin heavy chain (MHC) expression in both red (red gastrocnemius and soleus) and white (white gastrocnemius and TA) muscles were significantly decreased after brain ischemia. With at least moderate-dosage (200 ng/100 μl PBS) IGF 1 injection, the muscle weight and MHC protein could be restored in both red and white muscles resulting in better motor performance. However, the high-dose injection of IGF 1 (400 ng/100 μl PBS) did not result in further effects. IGF 1 increased the expression of p-Akt, but such effects were prevented by AG1024 resulting in muscle atrophy and poor motor function. In conclusion, peripheral application of IGF 1 not only prevented muscle atrophy but also enhanced motor function in rats with brain ischemia. The IGF 1-induced PI3K/Akt pathways are important for preventing muscle atrophy induced by brain ischemia.

1. Tsai, Y. W.,Yang, Y. R.,Chen, G. H.,Chang, H. C.,Wang, R. Y.(2008).The time window of intermittent hypoxia intervention after middle cerebral artery occlusion.Chinese J. Physiol.,51,324-328.
   連結：
2. Cantley, L. C.(2002).The phosphoinositide 3-kinase pathway.Science,296,1655-1657.
3. Carmeli, E.,Reznick, A. Z.,Coleman, R.,Carmeli, V.(2000).Muscle strength and mass of lower extremities in relation to functional abilities in elderly adults.Gerontology,46,249-257.
4. Choe, M. A.,An, G. J.,Lee, Y. K.,Im, J. H.,Choi-Kwon, S.,Heitkemper, M.(2004).Effect of inactivity and undernutrition after acute ischemic stroke in a rat hindlimb muscle model.Nurs. Res.,53,283-292.
5. Clarke, B. A.,Drujan, D.,Willis, M. S.,Murphy, L. O.,Corpina, R. A.,Burova, E.,Rakhilin, S. V.,Stitt, T. N.,Patterson, C.,Latres, E.,Glass, D. J.(2007).The E3 Ligase MuRF1 degrades myosin heavy chain protein in dexamethasone-treated skeletal muscle.Cell Metab.,6,376-385.
6. Cross, D. A.,Alessi, D. R.,Cohen, P.,Andjelkovich, M.,Hemmings, B. A.(1995).Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B.Nature,378,785-789.
7. Datta, S. R.,Brunet, A.,Greenberg, M. E.(1999).Cellular survival: a play in three Akts.Genes Dev.,13,2905-2927.
8. de Palma, L.,Marinelli, M.,Pavan, M.,Orazi, A.(2008).Ubiquitin ligases MuRF1 and MAFbx in human skeletal muscle atrophy.Joint Bone Spine,75,53-57.
9. DeVol, D. L.,Rotwein, P.,Sadow, J. L.,Novakofski, J.,Bechtel, P. J.(1990).Activation of insulin-like growth factor gene expression during work-induced skeletal muscle growth.Am. J. Physiol.,259,E89-E95.
10. Ding, Y.,Li, J.,Lai, Q.,Rafols, J. A.,Luan, X.,Clark, J.,Diaz, F. G.(2004).Motor balance and coordination training enhances functional outcome in rat with transient middle cerebral artery occlusion.Neuroscience,123,667-674.
11. Ferrando, A. A.,Lane, H. W.,Stuart, C. A.,Davis-Street, J.,Wolfe, R. R.(1996).Prolonged bed rest decreases skeletal muscle and whole body protein synthesis.Am. J. Physiol.,270,E627-E633.
12. Gomes, M. D.,Lecker, S. H.,Jagoe, R. T.,Navon, A.,Goldberg, A. L.(2001).Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy.Proc. Natl. Acad. Sci. U.S.A.,98,14440-14445.
13. Grossman, E. J.,Roy, R. R.,Talmadge, R. J.,Zhong, H.,Edgerton, V. R.(1998).Effects of inactivity on myosin heavy chain composition and size of rat soleus fibers.Muscle Nerve,21,375-389.
14. Jorgensen, L.,Jacobsen, B. K.(2001).Changes in muscle mass, fat mass, and bone mineral content in the legs after stroke: a 1 year prospective study.Bone,28,655-659.
15. Lai, K. M.,Gonzalez, M.,Poueymirou, W. T.,Kline, W. O.,Na, E.,Zlotchenko, E.,Stitt, T. N.,Economides, A. N.,Yancopoulos, G. D.,Glass, D. J.(2004).Conditional activation of akt in adult skeletal muscle induces rapid hypertrophy.Mol. Cell. Biol.,24,9295-9304.
16. Lawrence, E. S.,Coshall, C.,Dundas, R.,Stewart, J.,Rudd, A. G.,Howard, R.,Wolfe, C. D.(2001).Estimates of the prevalence of acute stroke impairments and disability in a multiethnic population.Stroke,32,1279-1284.
17. Lee, S.,Barton, E. R.,Sweeney, H. L.,Farrar, R. P.(2004).Viral expression of insulin-like growth factor-I enhances muscle hypertrophy in resistance-trained rats.J. Appl. Physiol.,96,1097-1104.
18. Locke, M.,Noble, E. G.,Atkinson, B. G.(1991).Inducible isoform of HSP70 is constitutively expressed in a muscle fiber type specific pattern.Am. J. Physiol.,261,C774-C779.
19. Menzies, S. A.,Hoff, J. T.,Betz, A. L.(1992).Middle cerebral artery occlusion in rats: a neurological and pathological evaluation of a reproducible model.Neurosurgery,31,100-107.
20. Minnaard, R.,Drost, M. R.,Wagenmakers, A. J.,van Kranenburg, G. P.,Kuipers, H.,Hesselink, M. K.(2005).Skeletal muscle wasting and contractile performance in septic rats.Muscle Nerve,31,339-348.
21. Nave, B. T.,Ouwens, M.,Withers, D. J.,Alessi, D. R.,Shepherd, P. R.(1999).Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation.Biochem. J.,344,427-431.
22. Rommel, C.,Bodine, S. C.,Clarke, B. A.,Rossman, R.,Nunez, L.,Stitt, T. N.,Yancopoulos, G. D.,Glass, D. J.(2001).Mediation of IGF-1-induced skeletal myotube hypertrophy by PI3K/Akt/mTOR and PI3K/Akt/GSK3 pathways.Nat. Cell Biol.,3,1009-1013.
23. Sacheck, J. M.,Ohtsuka, A.,McLary, S. C.,Goldberg, A. L.(2004).IGF-I stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1.Am. J. Physiol. Endocrinol. Metab.,287,E591-E601.
24. Schneider, R.,Gautier, J. C.(1994).Leg weakness due to stroke. Site of lesions, weakness patterns and causes.Brain,117,347-354.
25. Stitt, T. N.,Drujan, D.,Clarke, B. A.,Panaro, F.,Timofeyva, Y.,Kline, W. O.,Gonzalez, M.,Yancopoulos, G. D.,Glass, D. J.(2004).The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors.Mol. Cell,14,395-403.
26. Takahashi, T.,Ishida, K.,Itoh, K.,Konishi, Y.,Yagyu, K. I.,Tominaga, A.,Miyazaki, J. I.,Yamamoto, H.(2003).IGF-I gene transfer by electroporation promotes regeneration in a muscle injury model.Gene Ther.,10,612-620.
27. Vivanco, I.,Sawyers, C. L.(2002).The phosphatidylinositol 3-Kinase AKT pathway in human cancer.Nat. Rev. Cancer,2,489-501.
28. Yang, Y. R.,Wang, R. Y.,Wang, P. S.(2003).Early and late treadmill training after focal brain ischemia in rats.Neurosci. Lett.,339,91-94.
29. Yang, Y. R.,Wang, R. Y.,Wang, P. S.,Yu, S. M.(2003).Treadmill training effects on neurological outcome after middle cerebral artery occlusion in rats.Can. J. Neurol. Sci.,30,252-258.
30. Yarasheski, K. E.,Pak-Loduca, J.,Hasten, D. L.,Obert, K. A.,Brown, M. B.,Sinacore, D. R.(1999).Resistance exercise training increases mixed muscle protein synthesis rate in frail women and men ≥ 76 yr old.Am. J. Physiol.,277,E118-E125.
31. Zdanowicz, M. M.,Teichberg, S.(2003).Effects of insulin-like growth factor-1/binding protein-3 complex on muscle atrophy in rats.Exp. Biol. Med.,228,891-897.