Delineating Sex-dependent and Anatomic Decline of Motor Functions in the SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis

The transgenic SOD1G93A mouse model is the most widely used animal model of amyotrophic lateral sclerosis (ALS), a fatal disease of motor neuron degeneration. While genetic background influences onset and progression variability of motor dysfunction, the C57BL/6 background most reliably exhibits robust ALS phenotypes; thus, it is the most widely used strain in mechanistic studies. In this model, paresis begins in the hindlimbs and spreads rostrally to the forelimbs. Males experience earlier onset, greater disease severity, and shorter survival than females. However, the influence of sex on patterns of declining motor function between forelimbs and hindlimbs as well as among distinct, spinal-innervated muscle groups within each limb are not fully understood. To provide a higher resolution framework of degenerating motor function across the body, we conducted more comprehensive, limb-dependent and independent measures of motor decline over the course of disease. Subsequently, we compared the timing and intensity of these features across sex, and we consider to what extent these patterns are conserved in clinical observations from human ALS patients. We found male mice experienced earlier and less localized onset than females. We also report distinct motor features decline at different rates between sexes. Finally, mice showed differences in correlation between the decline of left- and right-side measures of the hindlimb. Consequently, our findings reinforce and refine the utility of the SOD1 mouse in modeling more highly resolved, sex-specific differences in ALS patient motor behavior. This may better guide preclinical studies in stratifying patients by sex and anatomical site of onset.