Sarcomeric dysfunction contributes to muscle weakness in facioscapulohumeral muscular dystrophy.
OBJECTIVE
To investigate whether sarcomeric dysfunction contributes to muscle weakness in facioscapulohumeral muscular dystrophy (FSHD).


METHODS
Sarcomeric function was evaluated by contractile studies on demembranated single muscle fibers obtained from quadriceps muscle biopsies of 4 patients with FSHD and 4 healthy controls. The sarcomere length dependency of force was determined together with measurements of thin filament length using immunofluorescence confocal scanning laser microscopy. X-ray diffraction techniques were used to study myofilament lattice spacing.


RESULTS
FSHD muscle fibers produced only 70% of active force compared to healthy controls, a reduction which was exclusive to type II muscle fibers. Changes in force were not due to changes in thin filament length or sarcomere length. Passive force was increased 5- to 12-fold in both fiber types, with increased calcium sensitivity of force generation and decreased myofilament lattice spacing, indicating compensation by the sarcomeric protein titin.


CONCLUSIONS
We have demonstrated a reduction in sarcomeric force in type II FSHD muscle fibers, and suggest compensatory mechanisms through titin stiffening. Based on these findings, we propose that sarcomeric dysfunction plays a critical role in the development of muscle weakness in FSHD.
Department of Neurology, Neuromuscular Centre Nijmegen, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. s.lassche@neuro.umcn.nl
Saskia
S
Lassche
Ger J M
GJ
Stienen
Tom C
TC
Irving
Silvère M
SM
van der Maarel
Nicol C
NC
Voermans
George W
GW
Padberg
Henk
H
Granzier
Baziel G M
BG
van Engelen
Coen A C
CA
Ottenheijm
D000328:Adult; D004594:Electrophysiology; D005455:Fluorescent Antibody Technique; D006801:Humans; D018613:Microscopy, Confocal; D018908:Muscle Weakness / Q000503:physiopathology*; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000503:physiopathology*; D012518:Sarcomeres; D014961:X-Ray Diffraction