Dystropathology Increases Energy Expenditure and Protein Turnover in the Mdx Mouse Model of Duchenne Muscular Dystrophy

Abstract

The skeletal muscles in Duchenne muscular dystrophy and the mdx mouse model lack functional dystrophin and undergo repeated bouts of necrosis, regeneration, and growth. These processes have a high metabolic cost. However, the consequences for whole body energy and protein metabolism, and on the dietary requirements for these macronutrients at different stages of the disease, are not well-understood. This study used juvenile (4- to 5- wk-old) and adult (12- to 14-wk-old) male dystrophic C57BL/10ScSn-mdx/J and age-matched C57BL/10ScSn/J control male mice to measure total and resting energy expenditure, food intake, spontaneous activity, body composition, whole body protein turnover, and muscle protein synthesis rates. In juvenile mdx mice that have extensive muscle damage, energy expenditure, muscle protein synthesis, and whole body protein turnover rates were higher than in age-matched controls. Adaptations in food intake and decreased activity were insufficient to meet the increased energy and protein needs of juvenile mdx mice and resulted in stunted growth. In (non-growing) adult mdx mice with less severe dystropathology, energy expenditure, muscle protein synthesis, and whole body protein turnover rates were also higher than in age-matched controls. Food intake was sufficient to meet their protein and energy needs, but insufficient to result in fat deposition. These data show that dystropathology impacts the protein and energy needs of mdx mice and that tailored dietary interventions are necessary to redress this imbalance. If not met, the resultant imbalance blunts growth, and may limit the benefits of therapies designed to protect and repair dystrophic muscles.

Muscle damage, metabolism, and oxidative stress in mdx mice: Impact of aerobic running

“…This supports our finding that treadmill exercise influences exercise capacity deleteriously, and also confirms results from previous research . After several weeks of exercise, mdx mice were using similar levels of oxygen as sedentary and wild‐type mice, but at significantly lower workloads, in line with research which showed that mdx mice have increased energy expenditure and protein turnover compared with wild‐type controls …”

“…21 After several weeks of exercise, mdx mice were using similar levels of oxygen as sedentary and wild-type mice, but at significantly lower workloads, in line with research which showed that mdx mice have increased energy expenditure and protein turnover compared with wild-type controls. 32 Myofiber necrosis and collagen scar formation remain hallmark features of dystrophic disease pathology. Necrotic muscle fibers become replaced with noncontractile connective tissue and cause a blunting in muscle function.…”

Taurine deficiency, synthesis and transport in the mdx mouse model for Duchenne Muscular Dystrophy

“…Another possibility is that these perturbations are a consequence of changes in metabolic demands of dystrophic muscles. Energy expenditure, muscle protein synthesis, and whole body protein turnover rates are considerably higher in mdx mice relative to age-matched controls (Radley-Crabb et al, 2014). It is plausible that the increase in metabolic demand is responsible for the lower cysteine content is in liver, plasma and muscle of 18 day old mdx mice relative C57 mice.…”

Lack of Dystrophin Affects Bronchial Epithelium in mdx Mice

“…In this context, the mdx mouse model is a useful intermediate step to assess the effects of training on dystrophic muscle (Grounds et al, 2008). Lack of dystrophin in mdx mice leads to cycles of muscle degeneration and regeneration (Radley-Crabb et al, 2014). While excessive or otherwise inappropriate activity may induce muscle damage and increase pathology in mdx mice (Brussee et al, 1997;De Luca et al, 2003;Okano et al, 2005) some protective effects of low-intensity or voluntary exercise (Hayes and Williams, 1996;Call et al, 2010;Baltgalvis et al, 2012;Gordon et al, 2014) have been reported.…”