title: Neprilysin participates in skeletal muscle regeneration and is accumulated in abnormal muscle fibres of inclusion body myositis.
abstract: Neprilysin (NEP, EP24.11), a metallopeptidase originally shown to modulate signalling events by degrading small regulatory peptides, is also an amyloid-beta- (Abeta) degrading enzyme. We investigated a possible role of NEP in inclusion body myositis (IBM) and other acquired and hereditary muscle disorders and found that in all myopathies NEP expression was directly associated with the degree of muscle fibre regeneration. In IBM muscle, NEP protein was also strongly accumulated in Abeta-bearing abnormal fibres. In vitro, during the experimental differentiation of myoblasts, NEP protein expression was regulated at the post-transcriptional level with a rapid increase in the early stage of myoblast differentiation followed by a gradual reduction thereafter, coincident with the progression of the myogenic programme. Treatment of differentiating muscle cells with the NEP inhibitor dl-3-mercapto-2-benzylpropanoylglycine resulted in impaired differentiation that was mainly associated with an abnormal regulation of Akt activation. Therefore, NEP may play an important role during muscle cell differentiation, possibly through the regulation, either directly or indirectly, of the insulin-like growth factor I-driven myogenic programme. In IBM muscle increased NEP may be instrumental in (i) reducing the Abeta accumulation in vulnerable fibres and (ii) promoting a repair/regenerative attempt of muscle fibres possibly through the modulation of insulin-like growth factor I-dependent pathways.
authors.affiliation: Department of Neuroscience, Catholic University, Rome, Italy. a.broccolini@rm.unicatt.it
authors.forename: Aldobrando
authors.initials: A
authors.lastname: Broccolini
authors.forename: Teresa
authors.initials: T
authors.lastname: Gidaro
authors.forename: Roberta
authors.initials: R
authors.lastname: Morosetti
authors.forename: Carla
authors.initials: C
authors.lastname: Gliubizzi
authors.forename: Tiziana
authors.initials: T
authors.lastname: Servidei
authors.forename: Mario
authors.initials: M
authors.lastname: Pescatori
authors.forename: Pietro A
authors.initials: PA
authors.lastname: Tonali
authors.forename: Enzo
authors.initials: E
authors.lastname: Ricci
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mirabella
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000378:metabolism; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D002453:Cell Cycle / Q000502:physiology; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003893:Desmin / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology*; D032446:Myoblasts; D009218:Myosins / Q000378:metabolism; D018979:Myositis, Inclusion Body / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015260:Neprilysin / Q000378:metabolism / Q000502:physiology*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D012038:Regeneration / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013875:Thiophanate / Q000494:pharmacology; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D003893:Desmin; D018969:Insulin-Like Growth Factor Binding Proteins; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D013875:Thiophanate; D003513:Cycloheximide; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D015260:Neprilysin; D009218:Myosins