Date Published: April 10, 2019
Publisher: Public Library of Science
Author(s): Erin M. Lloyd, Hongyang Xu, Robyn M. Murphy, Miranda D. Grounds, Gavin J. Pinniger, Atsushi Asakura.
Dysferlinopathies are a form of muscular dystrophy caused by gene mutations resulting in deficiency of the protein dysferlin. Symptoms manifest later in life in a muscle specific manner, although the pathomechanism is not well understood. This study compared the impact of dysferlin-deficiency on in vivo and ex vivo muscle function, and myofibre type composition in slow (soleus) and fast type (extensor digitorum longus; EDL) muscles using male dysferlin-deficient (dysf-/-) BLAJ mice aged 10 months, compared with wild type (WT) C57Bl/6J mice. There was a striking increase in muscle mass of BLAJ soleus (+25%) (p<0.001), with no strain differences in EDL mass, compared with WT. In vivo measures of forelimb grip strength and wheel running capacity showed no strain differences. Ex vivo measures showed the BLAJ soleus had faster twitch contraction (-21%) and relaxation (-20%) times, and delayed post fatigue recovery (ps<0.05); whereas the BLAJ EDL had a slower relaxation time (+11%) and higher maximum rate of force production (+25%) (ps<0.05). Similar proportions of MHC isoforms were evident in the soleus muscles of both strains (ps>0.05); however, for the BLAJ EDL, there was an increased proportion of type IIx MHC isoform (+5.5%) and decreased type IIb isoform (-5.5%) (ps<0.01). This identification of novel differences in the impact of dysferlin-deficiency on slow and fast twitch muscles emphasises the importance of evaluating myofibre type specific effects to provide crucial insight into the mechanisms responsible for loss of function in dysferlinopathies; this is critical for the development of targeted future clinical therapies.
Dysferlinopathies are a clinically heterogeneous group of muscle disorders that arise from mutations in the dysferlin gene (DYSF) that reduce expression of functional dysferlin protein . Clinically, dysferlinopathies are described as limb-girdle muscular dystrophy type 2B or Miyoshi myopathy, with initial weakness in the proximal limb girdle or distal limb muscles respectively , although gradations across phenotypes are now more widely recognised . Most patients with dysferlinopathy become wheelchair bound within 10–20 years after diagnosis, and currently there is no treatment.
The main findings of this study are that dysferlin-deficiency for male BLAJ mice aged 10 months (i) had a limited impact on our measures of in vivo muscle function, (ii) greatly increased the mass of BLAJ soleus muscles, and (iii) had myofibre type specific alterations of ex vivo muscle function for BLAJ soleus and EDL muscles. These findings are discussed in detail below.