title: More than a bystander: the contributions of intrinsic skeletal muscle defects in motor neuron diseases.
abstract: Spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), and spinal-bulbar muscular atrophy (SBMA) are devastating diseases characterized by the degeneration of motor neurons. Although the molecular causes underlying these diseases differ, recent findings have highlighted the contribution of intrinsic skeletal muscle defects in motor neuron diseases. The use of cell culture and animal models has led to the important finding that muscle defects occur prior to and independently of motor neuron degeneration in motor neuron diseases. In SMA for instance, the muscle specific requirements of the SMA disease-causing gene have been demonstrated by a series of genetic rescue experiments in SMA models. Conditional ALS mouse models expressing a muscle specific mutant SOD1 gene develop atrophy and muscle degeneration in the absence of motor neuron pathology. Treating SBMA mice by over-expressing IGF-1 in a skeletal muscle-specific manner attenuates disease severity and improves motor neuron pathology. In the present review, we provide an in depth description of muscle intrinsic defects, and discuss how they impact muscle function in these diseases. Furthermore, we discuss muscle-specific therapeutic strategies used to treat animal models of SMA, ALS, and SBMA. The study of intrinsic skeletal muscle defects is crucial for the understanding of the pathophysiology of these diseases and will open new therapeutic options for the treatment of motor neuron diseases.
authors.affiliation: Ottawa Hospital Research Institute, Regenerative Medicine Program Ottawa ON, Canada ; Department of Cellular and Molecular Medicine, University of Ottawa Ottawa, ON, Canada.
authors.forename: Justin G
authors.initials: JG
authors.lastname: Boyer
authors.affiliation: Ottawa Hospital Research Institute, Regenerative Medicine Program Ottawa ON, Canada ; Department of Cellular and Molecular Medicine, University of Ottawa Ottawa, ON, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Ferrier
authors.affiliation: Ottawa Hospital Research Institute, Regenerative Medicine Program Ottawa ON, Canada ; Department of Cellular and Molecular Medicine, University of Ottawa Ottawa, ON, Canada ; Department of Medicine, University of Ottawa Ottawa, ON, Canada.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Kothary
keywords: fusion defect; insulin-like growth factor 1; mouse models; myofiber degeneration; neuromuscular disease