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Title: LONG-TERM INSULIN-LIKE GROWTH FACTOR-I EXPRESSION IN SKELETAL MUSCLES ATTENUATES THE ENHANCED IN VITRO PROLIFERATION ABILITY OF THE RESIDENT SATELLITE CELLS IN TRANSGENIC MICE

Author
item CHAKRAVARTHY, MANU - UNIV OF TEXAS MED SCHOOL
item FIOROTTO, MARTA - BAYLOR COLLEGE OF MED
item SCHWARTZ, ROBERT - BAYLOR COLLEGE OF MED
item BOOTH, FRANK - UNIV MISSOURI-COLUMBIA

Submitted to: Mechanisms of Aging and Development
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/4/2001
Publication Date: 9/1/2001
Citation: Chakravarthy, M.V., Fiorotto, M.L., Schwartz, R.J., Booth, F.W. 2001. Long-term insulin-like growth factor-I expression in skeletal muscles attenuates the enhanced in vitro proliferation ability of the resident satellite cells in transgenic mice. Mechanisms of Ageing and Development. 122(12):1303-1320. Available: http://www.elsevier.com.

Interpretive Summary: Insulin-like growth factor I (IGF-I) is a hormone that is necessary for people and animals to grow properly. We know that overexpression of IGF-I for a month in the skeletal muscle of mice increases the ability of muscle satellite cells to multiply, which means greater muscle mass. However, we don't know whether this IGF-I benefit persists for a long time in elderly mice. This issue is important because, while this type of gene therapy has helped some patients' muscles, it would be optimal to know whether long-term administration of this hormone could provide the same benefit in old people. More than half of people above 85 years of age are weak because their muscles have deteriorated, so they must live in nursing homes to get the necessary help. Rejuvenating elderly people's muscles would improve their quality of life. For our investigation of this question, we used a special, genetically engineered mouse, called a transgenic mouse, that expressed very high levels of this hormone in their muscles. We found that 18 months of continuous overexpression led to a loss in the capability of the muscle satellite cells to multiply than we had observed in 1-month-old transgenic mice. In fact, the levels at 18 months in these transgenic mice went down to those seen in ordinary 18-month-old mice. Therefore, it appears that there is no further benefit to be gained from long-term doses of this hormone in the skeletal muscle of aged mice with regard to the retention of the initially enhanced muscle mass and improvement in the ability of the satellite cells to multiply. This is an important piece of work which will help researchers further explore the issue of the mechanisms underlying muscle atrophy with aging and potential ways to rebuild it.

Technical Abstract: Insulin-like growth factor-I (IGF-I) overexpression for 1-month in mouse skeletal muscle increases satellite cell proliferation potential. However, it is unknown whether this beneficial enhancement by IGF-I expression would persist over a longer-term duration in aged mice. This is an important issue to address if a prolonged course of IGF-I is to be used clinically in muscle-wasting conditions where satellite cells may become limiting. Using the IGF-I transgenic (IGF-I Tg) mouse that selectively expresses the IGF-I transgene in striated muscles, we found that 18-months of continuous IGF-I overexpression led to a loss in the enhanced in vitro proliferative capacity of satellite cells from Tg skeletal muscles. Also 18-month-old IGF-I Tg satellite cells lost the enhanced BrdU incorporation, greater pRb and Akt phosphorylations, and decreased p27Kip1 levels initially observed in cells from 1-month-old IGF-I Tg mice. The levels of those biochemical markers reverted to similar values seen in the 18-months WT littermates. These findings, therefore, suggest that there is no further beneficial effect on enhancing satellite cell proliferation ability with persistent long-term expression of IGF-I in skeletal muscles of these transgenic mice.