Pro-Insulin-Like Growth Factor-II Ameliorates Age-Related Inefficient Regenerative Response by Orchestrating Self-Reinforcement Mechanism of Muscle Regeneration.
Sarcopenia, age-related muscle weakness, increases the frequency of falls and fractures in elderly people, which can trigger severe muscle injury. Rapid and successful recovery from muscle injury is essential not to cause further frailty and loss of independence. In fact, we showed insufficient muscle regeneration in aged mice. Although the number of satellite cells, muscle stem cells, decreases with age, the remaining satellite cells maintain the myogenic capacity equivalent to young mice. Transplantation of young green fluorescent protein (GFP)-Tg mice-derived satellite cells into young and aged mice revealed that age-related deterioration of the muscle environment contributes to the decline in regenerative capacity of satellite cells. Thus, extrinsic changes rather than intrinsic changes in satellite cells appear to be a major determinant of inefficient muscle regeneration with age. Comprehensive protein expression analysis identified a decrease in insulin-like growth factor-II (IGF-II) level in regenerating muscle of aged mice. We found that pro- and big-IGF-II but not mature IGF-II specifically express during muscle regeneration and the expressions are not only delayed but also decreased in absolute quantity with age. Supplementation of pro-IGF-II in aged mice ameliorated the inefficient regenerative response by promoting proliferation of satellite cells, angiogenesis, and suppressing adipogenic differentiation of platelet derived growth factor receptor (PDGFR)α(+) mesenchymal progenitors. We further revealed that pro-IGF-II but not mature IGF-II specifically inhibits the pathological adipogenesis of PDGFRα(+) cells. Together, these results uncovered a distinctive pro-IGF-II-mediated self-reinforcement mechanism of muscle regeneration and suggest that supplementation of pro-IGF-II could be one of the most effective therapeutic approaches for muscle injury in elderly people.
Department of Regenerative Medicine, Research Institute, National Center for Geriatrics and Gerontology, Aichi, Japan.
Madoka
M
Ikemoto-Uezumi
Division for Therapies against Intractable Diseases, Institute for Comprehensive Medical Science, Fujita Health University, Aichi, Japan.
Akiyoshi
A
Uezumi
Division for Therapies against Intractable Diseases, Institute for Comprehensive Medical Science, Fujita Health University, Aichi, Japan.
Kunihiro
K
Tsuchida
Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
So-ichiro
S
Fukada
Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan.
Hiroshi
H
Yamamoto
Laboratory of Molecular Biology and Histochemistry, Fujita Health University Joint Research Laboratory, Aichi, Japan.
Naoki
N
Yamamoto
Department of Regenerative Medicine, Research Institute, National Center for Geriatrics and Gerontology, Aichi, Japan.
Kosuke
K
Shiomi
Department of Regenerative Medicine, Research Institute, National Center for Geriatrics and Gerontology, Aichi, Japan.
Naohiro
N
Hashimoto
D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000502:physiology*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology*; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism*
D011498:Protein Precursors; C066038:proinsulin-like growth factor II; D007335:Insulin-Like Growth Factor II
Aging; Pro-insulin-like growth factor-II; Regeneration; Skeletal muscle