A. E. KUDWA, Y. JIMENEZ, D. GOMEZ, A. SANCHEZ, R. STEVENSON, B. ALOSIO, R. MUSHLIN, K. CIRILLO, S. RAMBOZ
Duchenne muscular dystrophy (DMD) is a lethal X-linked neuromuscular disease caused by a mutation in the dystrophin gene, and the mdx mouse is the most widely used model of DMD used in preclinical therapeutic screening. Many neuromuscular diseases such as DMD are characterized by an exaggerated exercise-induced fatigue response, disproportionate to activity level, known as fatigability which is observed in both DMD patients and the mdx mouse. As such, we developed a hind limb fatigue challenge (HLFC) test utilizing postural fatigue and identified a robust, early in vivo fatigability phenotype in the mdx mouse. In the HLFC test, subjects are evaluated in a locomotor task, are then forced to stand on their hind limbs for an extended period of time, and are subsequently evaluated in the same locomotor task. Whereas other exercise paradigms such as the running wheel or treadmill can be used to elicit whole body fatigue incorporating more robust cardiopulmonary components, the HLFC test isolates the fatigue to the hindlimb muscles, and we observe consistent early differences in fatigability between mdx and control animals. However, as the mdx mouse exhibits substantial muscle regeneration leading to a mild progression of the disease, the extent of muscle pathology in sedentary adult mdx mice is low and running wheel or treadmill exercise are often used to exacerbate myofibre necrosis, biomarkers indicative of muscle damage, and behavioral deficits. Therefore, the current study directly compares cohorts of mice evaluated in the HLFC longitudinally with or without exercise in between HLFC testing ages. Ultimately, our goal is to develop a behavioral battery which will reliably capture neuromuscular deficits and provide for efficient and robust preclinical testing in the mdx mouse model of DMD. The effectiveness of currently used compounds with therapeutic value in DMD patients, such as prednisone, will be screened using the newly established efficacy study platform.