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: Stefan Hettwer, Pius Dahinden, Stefan Kucsera, Carlo Farina, Shaheen Ahmed, Ruggero Fariello, Michael Drey, Cornel Christian Sieber, Jan Willem Vrijbloed
• Journal: Experimental gerontology (Exp Gerontol) Vol. 48 Issue 1 Pg. 69-75 (Jan 2013) ISSN: 1873-6815 [Electronic] England
• PMID: 22433628 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Agrin
• Biomarkers
• Peptide Fragments
• Serine Proteinase Inhibitors
• Serine Endopeptidases
• neurotrypsin

Topics

• Adult
• Aged
• Aged, 80 and over
• Aging (blood, physiology)
• Agrin (blood, drug effects)
• Animals
• Biomarkers (blood)
• Case-Control Studies
• Female
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Transgenic
• Middle Aged
• Muscle Strength (physiology)
• Muscle, Skeletal (physiopathology)
• Peptide Fragments (blood)
• Sarcopenia (blood, physiopathology)
• Serine Endopeptidases (physiology)
• Serine Proteinase Inhibitors (pharmacology)
• Young Adult