Biomechanical and physiological investigations in the IBMPFD animal model
Inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD; OMIM 167320) is an autosomal dominant inherited multisystem disorder caused by mutations in the valosin-containing protein (VCP) gene. Knock-in mice expressing the common human p.R155H VCP mutation develop a progressive myopathy with ubiquitin-positive inclusion bodies, accumulation of abnormally shaped mitochondria in skeletal muscle and focal bone degradation reminiscent of Paget’s disease of bone. To further assess the physiological effects of this mutation in muscle, we compared the in vitro contractile properties of the extensor digitorum longus (EDL) (fast-twitch muscle) and soleus (slow-twitch muscle) from mice heterozygous for the p.R155H mutation in VCP and wild-type mice. Our results showed that fast-twitch muscle fibres isolated from VCPR155H/+ mutant mice ~12-15 months old not only fatigued faster and to a greater extent, but also recovered significantly slower and to a lesser degree than those of age-matched wild-type mice. Thereafter, the muscles seem to recover and by the time the mice were 27 months old, there was no difference in the fatigue resistance of mutant and wild type mice. These results suggest that VCP may be necessary for maintenance of glycolytic capacity in mouse fast-twitch muscle fibres at 12-15 months only. Investigation of oxidative capacity in 12 and 14 month old VCPR155H/+ mice revealed significantly lower mitochondrial enzyme activity (citrate synthase) in VCPR155H/+ mice at 14 months; concomitant with the reduction in fasttwitch fibre fatigue tolerance. Primary fibroblast cells isolated from our VCPR155H/+ mouse model showed reduced ability of mitochondrial networks to fragment when exposed to oxidative stress, indicating that intact VCP is required for the successful maintenance of mitochondrial network dynamics and quality control.
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