title: Elevated levels of a C-terminal agrin fragment identifies a new subset of sarcopenia patients.
abstract: Sarcopenia is a recently defined medical condition described as age-associated loss of skeletal muscle mass and function. Recently, a transgenic mouse model was described linking dispersal of the neuromuscular junction caused by elevated agrin degradation to the rapid onset of sarcopenia. These mice show a significant elevation of serum levels of a C-terminal agrin fragment (CAF) compared to wild-type littermates. A series of experiments was designed to ascertain the significance of elevated agrin degradation in the development of human sarcopenia. A quantitative Western blot method was devised to detect CAF in sera of humans. A first trial on consenting blood donors (n=169; age 19-74 years) detected CAF in the limited range of 2.76 ± 0.95 ng/ml. In sarcopenia patients (diagnosed according to clinical and instrumental standards) mean CAF levels were significantly elevated (p=9.8E10-9; n=73; age 65-87 years) compared to aged matched controls. Of all sarcopenia patients, 40% had elevated, non-overlapping CAF levels compared to controls. Evidence is presented for a pathogenic role of the agrin/neurotrypsin system in a substantial subset of sarcopenia patients. These patients are characterized by elevated CAF blood levels compared to aged-matched healthy volunteers suggesting the identification of an agrin-dependent form of sarcopenia. Elevated CAF levels in a large subpopulation of sarcopenic patients suggest the existence of a specific form of sarcopenia for which CAF could become a biomarker and a new target for therapeutic interventions. The feasibility of this approach was demonstrated by the development of a small molecule capable of inhibiting neurotrypsin in vitro and in vivo.
authors.affiliation: Neurotune AG, Wagistrasse 27a, Schlieren, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hettwer
authors.forename: Pius
authors.initials: P
authors.lastname: Dahinden
authors.forename: Stefan
authors.initials: S
authors.lastname: Kucsera
authors.forename: Carlo
authors.initials: C
authors.lastname: Farina
authors.forename: Shaheen
authors.initials: S
authors.lastname: Ahmed
authors.forename: Ruggero
authors.initials: R
authors.lastname: Fariello
authors.forename: Michael
authors.initials: M
authors.lastname: Drey
authors.forename: Cornel Christian
authors.initials: CC
authors.lastname: Sieber
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Vrijbloed
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000097:blood / Q000502:physiology; D018171:Agrin / Q000097:blood* / Q000187:drug effects; D000818:Animals; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D053580:Muscle Strength / Q000502:physiology; D018482:Muscle, Skeletal / Q000503:physiopathology; D010446:Peptide Fragments / Q000097:blood; D055948:Sarcopenia / Q000097:blood* / Q000503:physiopathology; D012697:Serine Endopeptidases / Q000502:physiology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D055815:Young Adult
chemical_list: D018171:Agrin; D015415:Biomarkers; D010446:Peptide Fragments; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; C108493:neurotrypsin