Lifetime Analysis of Skeletal Muscle Pathology in the Muscular Dystrophy X-Linked Mouse
Abstract
Duchenne muscular dystrophy (DMD) is an X-linked muscle wasting disease that affects 1:3500 males at birth. Mutations in the DMD gene alter the reading frame, preventing expression of functional dystrophin protein. Dystrophin functions to connect the intracellular cytoskeleton to the extracellular matrix, facilitating lateral transmission of force during muscle contraction. Without dystrophin, skeletal muscles are susceptible to repeated cycles of contraction-induced damage and repair. Eventually, repair mechanisms fail and muscle is replaced by fibrotic and adipose tissue, leading to muscle weakness, loss of ambulation and premature death.
The muscular dystrophy X-linked mouse (mdx) is the most commonly used preclinical model for DMD. Although disease progression in the mouse does not perfectly model the human disease, it shares many of the same pathological features. Early characterizations of the model reported severe pathology through early adulthood followed by disease stabilization. As a result, research in the mdx mouse has largely neglected to describe pathology in aged animals.
The overarching goal of these studies is to improve the understanding of the mdx mouse model by tracking pathological features of the disease throughout life. We performed a thorough characterization of myofiber pathology in mdx mice from 2 weeks to 2 years of age. Using unique preparations to analyze mdx tissue from a new perspective, we identify a previously underappreciated feature of mdx pathology and extend the knowledge of hallmark features by tracking them throughout life. We report that individual mdx muscle fibers undergo progressive hypertrophy that continues through the lifespan. Despite massive hypertrophy on the myofiber level, we report no hypertrophy on the muscle level. These seemingly contradictory findings are explained by previously underappreciated myofiber loss in mdx mice. We therefore conclude that the utility of the mdx mouse in testing therapeutics is target dependent. Specifically, the mdx mouse is an excellent model for a therapeutic intending to prevent myofiber loss, but a poor model for one aimed at inducing myofiber hypertrophy. During the generation of these findings we improved the utility of tissue clearing techniques in skeletal muscles by characterizing compatibility with neuromuscular junction markers useful for the study of neuromuscular disease.
Subject
dystrophyCitation
Massopust, Ryan Thomas (2020). Lifetime Analysis of Skeletal Muscle Pathology in the Muscular Dystrophy X-Linked Mouse. Doctoral dissertation, Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /191757.