Thermoneutral Housing and a Western Diet Combination Exacerbates Dysferlin-Deficient Muscular Dystrophy

Area of Science:

• Biomedical Science
• Muscle Physiology
• Metabolic Research

Background:

• Muscular dystrophy (MD) mouse models often exhibit mild phenotypes, limiting therapeutic development.
• Metabolic abnormalities are increasingly recognized as potential contributors to MD progression.
• Thermoneutral (TN) housing and Western diets (WD) significantly impact metabolic parameters.

Purpose of the Study:

• To investigate if combined TN housing and WD exacerbate muscle wasting in dysferlin-deficient BLAJ mice, a model for limb-girdle MD type 2b (LGMD2b).
• To assess the impact of environmental and dietary factors on MD pathogenesis in a relevant animal model.

Main Methods:

• BLAJ and wild-type (WT) mice were housed at TN or room temperature (RT) and fed WD or chow for 9 months.
• Evaluated ambulatory function, skeletal muscle histology, and protein expression via Western blotting.

Main Results:

• Combined TN and WD significantly worsened ambulatory function in BLAJ mice compared to RT/chow conditions (p < 0.001).
• Observed up to a 4.1-fold increase in fat infiltration in quadriceps and gastrocnemius muscles.
• Detected decreased autophagy (LC3BII/LC3BI ratio) and increased AKT/S6 phosphorylation, indicating impaired cellular clearance.

Conclusions:

• The combination of TN housing and WD exacerbates muscle wasting and fat infiltration in a rodent model of LGMD2b.
• This finding enhances the utility of rodent models for studying human MD and understanding the role of metabolic dysfunction in muscle wasting.