Musculoskeletal ECM-induced reprogramming of the metabolic system
Dr. Eva Hucklenbruch-Rother
University Hospital for Pediatrics and Adolescent Medicine
Faculty of Medicine, University of Cologne
Kerpener Str. 62, 50937 Cologne
Prof. Dr. Jörg Dötsch
University Hospital for Pediatrics and Adolescent Medicine
Faculty of Medicine, University of Cologne
Kerpener Str. 62, 50937 Cologne
Prof. Dr. Gerhard Sengle
University Hospital for Pediatrics and Adolescent Medicine
Faculty of Medicine, University of Cologne
Joseph-Stelzmann-Str. 52, 50931 Cologne
Summary
The involvement of the extracellular matrix (ECM) proteins fibrillin and collagen VI in the regulation of body fat is intuitive, since most mutations in the fibrillin (FBN1, FBN2) or collagen VI genes (COL6A1, COL6A2, COL6A3) result in syndromes characterized by a slender habitus with little subcutaneous fat. In 2016, the identification of the C-terminal cleavage product of profibrillin-1, termed asprosin, provided an explanation for the strong genotype-phenotype correlation in patients with FBN1 3’ end mutations. Asprosin is released by the fibrillin-1 producing connective tissue, stimulates rapid hepatic glucose release and activates hunger-promoting neurons in the hypothalamus.
Moreover, the C-terminal cleavage product of the collagen VI alpha 3 chain endotrophin was described to affect body weight, body fat and glucose homeostasis. We therefore hypothesize that the musculoskeletal system is involved in metabolic reprogramming by releasing fragments from muscle, cartilage, and bone triggered by connective tissue disease or exercise-induced ECM break down (“biomechanical reprogramming”).
To test this hypothesis, we will identify mechanisms of asprosin/ endotrophin production, storage, and release in skeletal muscle, cartilage and bone. Translation into other mouse models and human cohorts of musculoskeletal and metabolic disease will allow assessing the diagnostic, preventive and therapeutic potential of asprosin/ endotrophin.