title: Suite of clinically relevant functional assays to address therapeutic efficacy and disease mechanism in the dystrophicmdxmouse.
abstract: Duchenne muscular dystrophy (DMD) is a progressive primary myodegenerative disease caused by a genetic deficiency of the 427-kDa 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 homologs to the design of informative clinical trials. Here we describe novel phenotypic assays which when applied to themdxmouse resemble recently used primary end points for DMD clinical trials. 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. 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. For example, the dramatic loss of volitional movement following a novel, standardized grip test distinguishes control mice frommdxmice by a 17.4-fold difference of the means (3.5 ± 2.2 vs. 60.9 ± 12.1 units of activity, respectively; effect size 1.99). The findings have both mechanistic and translational implications of potential significance to the fields of basic myology and neuromuscular therapeutics.NEW & NOTEWORTHYThis study uses novel phenotypic assays which when applied to themdxmouse resemble recently used primary end points for DMD clinical trials. A measurable distinction between dystrophic and control mice was seen at early time points in vivo compared with invasive muscle studies performed ex vivo. These assays shed light on normal and pathological responses to muscular exertion and have significant mechanistic and translational implications for the fields of basic myology and neuromuscular therapeutics.
authors.affiliation: Perelman School of Medicine & Pennsylvania Muscle Institute, University of Pennsylvania, Philadelphia, Pennsylvania; and.
authors.forename: Yafeng
authors.initials: Y
authors.lastname: Song
authors.affiliation: Perelman School of Medicine & Pennsylvania Muscle Institute, University of Pennsylvania, Philadelphia, Pennsylvania; and.
authors.forename: Shira T
authors.initials: ST
authors.lastname: Rosenblum
authors.affiliation: Perelman School of Medicine & Pennsylvania Muscle Institute, University of Pennsylvania, Philadelphia, Pennsylvania; and.
authors.forename: Leon
authors.initials: L
authors.lastname: Morales
authors.affiliation: Perelman School of Medicine & Pennsylvania Muscle Institute, University of Pennsylvania, Philadelphia, Pennsylvania; and.
authors.forename: Mihail
authors.initials: M
authors.lastname: Petrov
authors.affiliation: Perelman School of Medicine & Pennsylvania Muscle Institute, University of Pennsylvania, Philadelphia, Pennsylvania; and.
authors.forename: Christopher
authors.initials: C
authors.lastname: Greer
authors.affiliation: Perelman School of Medicine & Pennsylvania Muscle Institute, University of Pennsylvania, Philadelphia, Pennsylvania; and.
authors.forename: Samantha
authors.initials: S
authors.lastname: Globerman
authors.affiliation: Perelman School of Medicine & Pennsylvania Muscle Institute, University of Pennsylvania, Philadelphia, Pennsylvania; and hstedman@mail.med.upenn.edu.|Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania.
authors.forename: Hansell H
authors.initials: HH
authors.lastname: Stedman
mesh_terms: D000818:Animals; D023381:Endpoint Determination / Q000379:methods*; D005080:Exercise Test / Q000379:methods*; D051379:Mice; D018101:Mice, Inbred mdx; D009136:Muscular Dystrophies / Q000175:diagnosis / Q000503:physiopathology* / Q000628:therapy*; D017063:Outcome Assessment, Health Care / Q000379:methods*; D015203:Reproducibility of Results; D012129:Respiratory Function Tests / Q000379:methods*; D012680:Sensitivity and Specificity; D016896:Treatment Outcome
keywords: Duchenne muscular dystrophy; open field; running wheel; whole limb force test