Insulin-like growth factor I in inclusion-body myositis and human muscle cultures.
Possible pathogenic mechanisms of sporadic inclusion-body myositis (sIBM) include abnormal production and accumulation of amyloid beta (A beta), muscle aging, and increased oxidative stress. Insulin-like growth factor I (IGF-I), an endocrine and autocrine/paracrine trophic factor, provides resistance against A beta toxicity and oxidative stress in vitro and promotes cell survival. In this study we analyzed the IGF-I signaling pathway in sIBM muscle and found that 16.2% +/- 2.5% of nonregenerating fibers showed increased expression of IGF-I, phosphatidylinositide 3'OH-kinase, and Akt. In the majority of sIBM abnormal muscle fibers, increased IGF-I mRNA and protein correlated with the presence of A beta cytoplasmic inclusions. To investigate a possible relationship between A beta toxicity and IGF-I upregulation, normal primary muscle cultures were stimulated for 24 hours with the A beta(25-35) peptide corresponding to the biologically active domain of A beta. This induced an increase of IGF-I mRNA and protein in myotubes at 6 hours, followed by a gradual reduction thereafter. The level of phosphorylated Akt showed similar changes. We suggest that in sIBM. IGF-I overexpression represents a reactive response to A beta toxicity, possibly providing trophic support to vulnerable fibers. Understanding the signaling pathways activated by IGF-I in sIBM may lead to novel therapeutic strategies for the disease.
Broccolini
Aldobrando
A
Department of Neuroscience, Catholic University, Rome, Italy. a.broccolini@rm.unicatt.it
Ricci
Enzo
E
Pescatori
Mario
M
Papacci
Manuela
M
Gliubizzi
Carla
C
D'Amico
Adele
A
Servidei
Serenella
S
Tonali
Pietro
P
Mirabella
Massimiliano
M
D016229:Amyloid beta-Peptides / Q000633:toxicity; D002478:Cells, Cultured; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000096:biosynthesis*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D018979:Myositis, Inclusion Body / Q000378:metabolism* / Q000473:pathology*; D010446:Peptide Fragments / Q000633:toxicity
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D007334:Insulin-Like Growth Factor I