Donders Institute for Brain, Cognition and Behaviour
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Thesis defense Saskia Lassche (Donders series 477)

16 December 2020

Promotors: prof. dr. B. van Engelen, prof. dr. C. Ottenheijm
Co-promotor: dr. N. Voermans

Contractile function in facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common hereditary muscle disorders. FSHD is caused by expression of DUX4, a transcription factor that activates genes that are normally not expressed in mature skeletal muscle. DUX4 expression damages muscle tissue through atrophy, fibrosis and severe fatty infiltration. Specific force, i.e. the amount of force generated per unit of muscle tissue, is also impaired in FSHD.
This thesis investigates potential causes of reduced quadriceps specific force in FSHD, with a particular emphasis on muscle fiber contractile function. Additional questions are whether changes in muscle fiber contractile function are the result of FSHD specific pathology, or a physiological adaptation to muscle disease in general.
The findings in this thesis show that atrophy and fatty infiltration reduce the amount of contractile tissue in patients with severe FSHD, whereas specific force is reduced in patients with mild and severe disease. Single muscle fiber studies show that reduced quadriceps specific force in FSHD is not caused by sarcomeric dysfunction. Studies of in vivo and ex vivo contractile function in two other muscle disorders, inclusion body myositis (IBM) and oculopharyngeal muscular dystrophy (OPMD) show that these disorders have distinct contractile profiles.
Increased insight into the mechanisms that influence contractile function in FSHD and other muscle disorders will inspire new treatment approached and improve our understanding of the muscles that move us.