Pseudoachondroplasia (
PSACH) and
multiple epiphyseal dysplasia (MED) are skeletal disorders resulting from mutations in COMP,
matrilin-3 or
collagen IX and are characterised by short-limbed
dwarfism and premature
osteoarthritis. Interestingly, recent reports suggest patients can also manifest with
muscle weakness. Here we present a detailed analysis of two mouse models of the
PSACH/MED disease spectrum; ΔD469 T3-COMP (
PSACH) and V194D
matrilin-3 (MED). In grip test experiments T3-COMP mice were weaker than wild-type littermates, whereas V194D mice behaved as controls, confirming that short-limbed
dwarfism alone does not contribute to
PSACH/MED-related
muscle weakness. Muscles from T3-COMP mice showed an increase in centronuclear fibers at the myotendinous junction. T3-COMP tendons became more lax in cyclic testing and showed thicker
collagen fibers when compared with wild-type tissue;
matrilin-3 mutant tissues were indistinguishable from controls. This comprehensive study of the
myopathy associated with
PSACH/MED mutations enables a better understanding of the
disease progression, confirms that it is genotype specific and that the limb weakness originates from muscle and tendon pathology rather than short-limbed
dwarfism itself. Since some patients are primarily diagnosed with neuromuscular symptoms, this study will facilitate better awareness of the differential diagnoses that might be associated with the
PSACH/MED spectrum and subsequent care of
PSACH/MED patients.