Investigating why glucocorticoids have adverse effects on dysferlinopathy: molecular analyses after Dexamethasone treatment in BLAJ mice at 2 ages


Ultra-Rare myopathies and dystrophies (<1:100,000 worldwide)

Poster Number: 116


Miranda Grounds, PhD, Erin Lloyd, Rachael Crew, Robyn Murphy, vanessa Haynes, Matthew Watt


1. University of Western Australia, 2. University of Western Australia, 3. University of Western Australia, 4. LaTrobe University, 5. University of Melbourne, 6. University of Melbourne

Background. We have recently described striking changes in lipid metabolism and lipidomics in the dysferlin-deficient (dysf-/-) BLAJ mouse model of Limb Girdle Muscular Dystrophy Type 2B (LGMD2B) (Haynes et al., 2019. PMID: 31203232) and also differences in the impact of dysferlin-deficiency on slow (soleus) and fast (EDL) muscles (Lloyd et al., 2019. PMID: 30970035). We combine this perspective with the fact that Glucocorticoids (GCs) have long-term adverse effects on patients with dysferlinopathy, with loss of muscle strength.
Objective. To investigate the molecular basis for adverse effects of GCs on dysf-/ muscles.
Approach. The GC Dexamethasone (Dex) was administered to male BLAJ and normal wild type (WT) mice in vivo and in vitro. Dex acetate (0.5-0.75μg/ml) was provided in drinking water for up to 5 weeks, with mice sampled at 5 or 10 months (n=8 mice/group): this resulted in 8 groups of mice for Dex-treated and control untreated BLAJ and WT mice at 2 ages. Analysis included assessment of the phenotype of all mice, and RT-PCR quantification of selected gene expression levels in muscles.
Results This short-term GC treatment did not significantly affect body mass but significantly increased soleus mass in the old WT and BLAJ mice. Dex significantly increased glycogen content in the BLAJ soleus, with marked effects on proteins related to metabolism and calcium handling in BLAJ soleus and EDL muscles. Dex also altered RNA expression of metabolism and immune function genes in psoas and quadriceps muscles and liver, with more pronounced effects in older BLAJ mice.
Conclusions. These data provide new insight into molecular disturbances in slow and fast skeletal muscles due to dysferlin-deficiency and the adverse effects of GCs on LGMD2B.