Deletion of Murine <i>SMN</i> Exon 7 Directed to Skeletal Muscle Leads to Severe Muscular Dystrophy

TLDR

Spinal muscular atrophy (SMA) is characterized by degeneration of spinal cord motor neurons leading to muscle paralysis and is caused by mutations in the survival motor neuron gene (SMN). The authors aimed to determine whether a SMN gene defect in skeletal muscle contributes to SMA pathogenesis by generating a muscle‑specific SMN exon 7 knockout using a Cre‑loxP system, thereby providing a model to elucidate underlying mechanisms. They created a muscle‑specific SMN exon 7 knockout in mice by employing Cre‑loxP recombination to restrict the deletion to skeletal muscle. Muscle‑specific SMN exon 7 knockout mice display severe dystrophic muscle necrosis, paralysis, and death, with elevated creatine kinase, Evans blue dye uptake, reduced dystrophin, increased utrophin, indicating sarcolemma destabilization, and suggesting that skeletal muscle plays a primary role in SMA pathology and may inform therapeutic strategies.

Abstract

Spinal muscular atrophy (SMA) is characterized by degeneration of motor neurons of the spinal cord associated with muscle paralysis and caused by mutations of the survival motor neuron gene (SMN). To determine whether SMN gene defect in skeletal muscle might have a role in SMA pathogenesis, deletion of murine SMN exon 7, the most frequent mutation found in SMA, has been restricted to skeletal muscle by using the Cre-loxP system. Mutant mice display ongoing muscle necrosis with a dystrophic phenotype leading to muscle paralysis and death. The dystrophic phenotype is associated with elevated levels of creatine kinase activity, Evans blue dye uptake into muscle fibers, reduced amount of dystrophin and upregulation of utrophin expression suggesting a destabilization of the sarcolemma components. The mutant mice will be a valuable model for elucidating the underlying mechanism. Moreover, our results suggest a primary involvement of skeletal muscle in human SMA, which may contribute to motor defect in addition to muscle denervation caused by the motor neuron degeneration. These data may have important implications for the development of therapeutic strategies in SMA.