Insulin signaling and metabolism in facioscapulohumeral muscular dystrophy


FSHD is characterized by muscle weakness in an initially restricted and characteristic distribution, starting in the face, and continuing sequentially to scapular fixator, humeral, truncal, and lower-extremity muscles with wasting and fatigueability. FSHD is autosomal-dominant inherited and caused by deletion of a repetitive element on 4q35 known as D4Z4. This deletion leads to overly active genes including FSHD related gene (FRG)1. FRG1 is located 120 kb from the D4Z4 repeats and encodes an evolutionarily highly conserved nuclear protein that may play a role in RNA biogenesis. FRG1 is crucial for angiogenesis. FSHD has also been associated with dysfunction of adenine nucleotide translocase (ANT1) and therefore altered mitochondrial function. Impaired differentiation of myoblasts is also present in affected muscles and a genome-wide mRNA-scan suggested that the insulin receptor pathway might be dysregulated. Despite the apparent impact of metabolism and specifically the insulin signaling cascade in the differentiation and regeneration of muscle, this issue has not yet been investigated in FSHD and other muscle dystrophies. We found signs of insulin resistance in four FSHD patients. Therefore, we hypothesize that FSHD is associated 1) with insulin resistance, which may contribute to disturbed muscle hemodynamics and muscle differentiation/regeneration, and 2) with impaired vascularization of skeletal muscle which can be improved by a graded exercise program.
Head of Project:

Dr. med. Michael Boschmann
Charité - Universitätsmedizin Berlin
Department of Internal Medicine, Nephrology and Hypertensiology CBB
Tel. 450-540241
Fax 450-540920
michael.boschmann@charite.de
Additional Head of Project:

Prof. Dr. Joachim Spranger
Begin/End of Project:

04/2010 - 09/2014
Funded by:

Deutsche Forschungsgemeinschaft e.V.
Online-Information:

www.muskelforschung.de
Publications:

Tawil RM, Van Der Maarel S. Facioscapulohumeral muscular dystrophy. Muscle Nerve 2006; 34: 1-15 Pakula A, Mähler A, Schmidt S, Luft FC, Spuler S, Boschmann M. Facio-scapulohumeral muscular dystrophy, glucose metabolism and insulin resistance. 4th International Congress of Myology, Lille, France, May 9-13, 2011 Luedtke A, Boschmann M, Colpe C, Engeli S, Adams F, Birkenfeld AL, Haufe S, Rahn G, Luft FC, Schmidt HH, Jordan J. Thiazolidinedione Response in Familial Lipodystrophy Patients with LMNA Mutations: A Case Series. Horm Metab Res. 2012 Jan 24. [Epub ahead of print] Boschmann M, Engeli S, Moro C, Luedtke A, Adams F, Gorzelniak K, Rahn G, Mähler A, Dobberstein K, Krüger A, Schmidt S, Spuler S, Luft FC, Smith SR, Schmidt HH-J, Jordan J: LMNA mutations, skeletal muscle lipid metabolism, and insulin resistance. J Clin Endocrinol Metab 2010; 95:1634-1643