Low levels of Survival Motor Neuron protein are sufficient for normal muscle function in the SMNδ7 mouse model of SMA

Abstract

Spinal Muscular Atrophy (SMA) is an autosomal recessive disorder characterized by loss of lowermotor neurons. SMA is caused by deletion or mutation of the SurvivalMotor Neuron 1 (SMN1) gene and retention of the SMN2 gene. The loss of SMN1 results in reduced levels of the SMN protein. SMN levels appear to be particularly important in motor neurons; however SMN levels above that produced by two copies ofSMN2have been suggested to be important in muscle. Studying the spatial requirement ofSMNis important in both understanding how SMN deficiency causes SMA and in the development of effective therapies. Using Myf5-Cre, a musclespecific Cre driver, and the Cre-loxP recombination system, we deleted mouse Smn in the muscle of mice with SMN2 and SMNδ7 transgenes in the background, thus providing lowlevel of SMNin themuscle. As a reciprocal experiment, we restored normal levels of SMN in themusclewith lowSMNlevels in all other tissues. We observed that decreasing SMNin themuscle has no phenotypic effect. Thiswas corroborated bymuscle physiology studieswith twitch force, tetanic and eccentric contraction all being normal. In addition, electrocardiogramand muscle fiber size distributionwere also normal. Replacement of Smn inmuscle did not rescue SMA mice. Thus the muscle does not appear to require high levels of SMN above what is produced by two copies of SMN2 (and SMNδ7).