Role of plasminogen activator inhibitor-1 in glucocorticoid-induced muscle change in mice.
We recently revealed that plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor, is involved in diabetes, osteoporosis and muscle wasting induced by glucocorticoid (GC) treatment in mice. In the present study, we investigated the detailed mechanisms by which GC induces muscle wasting through PAI-1 in vivo and in vitro. PAI-1 deficiency suppressed the mRNA levels of atrogin1 and muscle RING-Finger Protein 1 (MuRF1), ubiquitin ligases leading to muscle degradation, elevated by GC treatment in the gastrocnemius muscle of mice. In vitro study revealed that active PAI-1 treatment augmented the increase in atrogin1 mRNA levels enhanced by dexamethasone (Dex) in mouse myoblastic C2C12 cells. Moreover, a reduction in endogenous PAI-1 level by siRNA suppressed the mRNA levels of atrogin1 and MuRF1 enhanced by Dex in C2C12 cells. In contrast, a reduction in endogenous PAI-1 levels and active PAI-1 did not affect the phosphorylations of Akt and p70S6 kinase nor myogenic differentiation with or without Dex in C2C12 cells. In addition, PAI-1 deficiency blunted IGF-1 mRNA levels decreased by GC treatment in the gastrocnemius muscle of mice, although neither active PAI-1 nor a reduction in endogenous PAI-1 levels affected the levels of IGF-1 mRNA in C2C12 cells in the presence of Dex. In conclusion, our data suggest that paracrine PAI-1 is involved in GC-induced muscle wasting through the enhancement of muscle degradation in mice.
Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan.
Yukinori
Y
Tamura
Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan.
Naoyuki
N
Kawao
Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan.
Takeshi
T
Shimoide
Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan.
Kiyotaka
K
Okada
Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan.
Osamu
O
Matsuo
Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan. hkaji@med.kindai.ac.jp.
Hiroshi
H
Kaji
D000818:Animals; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006474:Hemorrhagic Disorders / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D018345:Mice, Knockout; D024510:Muscle Development / Q000187:drug effects; D009124:Muscle Proteins / Q000096:biosynthesis; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects
D005938:Glucocorticoids; D009124:Muscle Proteins; D017395:Plasminogen Activator Inhibitor 1; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone
Glucocorticoid; Insulin-like growth factor-1; Muscle; Muscle wasting; Plasminogen activator inhibitor-1