Suite of Clinically Relevant Functional Assays to Address Therapeutic Efficacy and Disease Mechanism in the Dystrophic mdx Mouse

Duchenne muscular dystrophy (DMD) is a progressive primary myodegenerative disease caused by a genetic deficiency of the 427 KD cytoskeletal protein dystrophin. Despite its single-gene etiology, DMD's complex pathogenesis remains poorly understood, complicating the extrapolation from results of preclinical studies in genetic homologues to the design of informative clinical trials. Here we describe novel phenotypic assays which when applied to the mdx mouse resemble recently used primary endpoints for DMD clinical trials. A common feature of these physiological assays is the precise tracking and analysis of volitional movement, thereby optimizing the relevance to clinical tests. Unexpectedly, the measurable biological distinction between dystrophic and control mice at early time points in the disease process is better resolved with these tests than with the majority of previously used, labor-intensive studies of individual muscle function performed ex vivo. The most extreme example, the abrupt loss of volitional movement following a novel, standardized grip test, distinguishes control 100% (60.9 ± 12.1 units of activity) from mdx 6% (3.5 ± 2.2 units of activity) mice in groups of 12 with a p value of p<0.0001. By coupling force transduction, high precision motion tracking, and respiratory measurements we have achieved a suite of integrative physiological tests that provide novel insights regarding normal and pathological responses to muscular exertion. The findings have both mechanistic and translational implications of potential significance to the fields of basic myology and neuromuscular therapeutics.

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