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.
Highlights
Everything from physical exercise to daily chores and even breathing depends on force generated by skeletal muscles
The clinical severity of Spinal muscular atrophy (SMA) is categorized into 4 main types, which vary in their time of onset and expected prognosis
Castration of spinal-bulbar muscular atrophy (SBMA) model mice prevents any phenotype while treating female animals with testosterone exacerbates the phenotype (Katsuno et al, 2002). These results demonstrate that disease manifestations are androgen-dependent and this explains the gender bias observed in SBMA patients
Summary
Everything from physical exercise to daily chores and even breathing depends on force generated by skeletal muscles. Spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), and spinal-bulbar muscular atrophy (SBMA) are examples of such motor neuron diseases. Use of both cell culture and conditional mouse models has revealed defects in skeletal muscle that occur in the absence of defective motor neurons. Such studies highlight a potential contribution of skeletal muscle defects to the symptoms of SMA, ALS, and SBMA patients. These findings have major implications for the development of therapeutics for these diseases. We discuss the latest findings regarding intrinsic muscle defects as well as muscle-specific therapeutic strategies to treat SMA, ALS, and SBMA
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