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Research Project: MOLECULAR, CELLULAR, AND REGULATORY ASPECTS OF NUTRITIONAL METABOLISM DURING CHILDHOOD DEVELOPMENT

Location: Children's Nutrition Research Center

Title: Dystropathology increases energy expenditure and protein turnover in the Mdx mouse model of Duchenne muscular dystrophy

Author
item Radley-crabb, Hannah - University Of Western Australia
item Marini, Juan - Children'S Nutrition Research Center (CNRC)
item Sosa, Horacio - Children'S Nutrition Research Center (CNRC)
item Castillo, Liliana - Children'S Nutrition Research Center (CNRC)
item Grounds, Miranda - University Of Western Australia
item Fiorotto, Marta - Children'S Nutrition Research Center (CNRC)

Submitted to: PLoS One
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/17/2014
Publication Date: 2/19/2014
Citation: Radley-Crabb, H.G., Marini, J.C., Sosa, H.A., Castillo, L.I., Grounds, M.D., Fiorotto, M.L. 2014. Dystropathology increases energy expenditure and protein turnover in the Mdx mouse model of Duchenne muscular dystrophy. PLoS One. 9(2):e89277.

Interpretive Summary: The skeletal muscles in growing boys with Duchenne muscular dystrophy (DMD) undergo a constant progression of muscle death, inflammation, and attempts at regeneration. These processes come with a considerable cost for both energy and protein that must be provided in addition to the standard energy and protein needs of growing boys. Should these adaptations be insufficient to counterbalance the increased needs for these nutrients, the maintenance of the muscles and normal growth and body composition become compromised, with the possibility of exacerbating the primary degenerative effects of the disease. This study documents the consequences of muscular dystrophy for whole body energy and protein metabolism in the mdx mouse model of muscular dystrophy in which the effects of the disease are similar, if not as extreme as in DMD boys. Both young growing dystrophic mice (when the disease is most active) and adult dystrophic mice (when growth has ceased and the disease is less severe) were studied. The results demonstrated that muscular dystrophy significantly increased amino acid catabolism and basal energy expenditure at all ages. Despite adaptations in physical activity energy expenditure, growth in the young mice was blunted indicating that the amount of both protein and energy that they ate was not sufficient to meet their increased needs. In the older mice, fat deposition was absent. Although the results in the mouse model cannot be translated directly to humans, they highlight the possibility that the composition and amount of diet consumed can mitigate or further aggravate the consequences of the DMD genetic lesion. These results also imply that if the nutrient needs of the humans and animal models of DMD are not met, the benefits of molecular and pharmacological therapies designed to protect and repair dystrophic muscle may have sub-optimal efficacy.

Technical 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.