UC San Diego

Many species that run or leap across sparsely vegetated habitats, including hooved animals like horses and deer, evolved the severe reduction or complete loss of foot muscles as skeletal elements elongated and digits were lost. Although entire groups of muscles were lost repeatedly throughout vertebrate evolution, the developmental mechanisms remain unknown. Here, we investigate the cellular and molecular mechanisms underlying the natural loss of intrinsic foot muscles in a small bipedal rodent, the lesser Egyptian jerboa (Jaculus jaculus). Although adults have no muscles in their feet, myoblast migration and fusion proceed normally to form multinucleated myofibers in newborn animals that rapidly disappear soon after birth. We were therefore surprised to find no evidence of apoptotic or necrotic cell death and no stimulation of a local immune response during stages of peak myofiber loss, countering well-supported assumptions of developmental tissue remodeling. We instead see hallmarks of muscle atrophy, including an ordered disassembly of the sarcomere apparatus associated with upregulation of the E3 ubiquitin ligases, MuRF1 and Atrogin-1. Transcriptome profiling of newborn jerboa foot muscle showed differentially expressed genes significant overlap with models of muscle loss such as cancer-induced cachexia and botulinum-toxin-induced muscle loss. We propose that the natural loss of muscle, which remodeled foot anatomy during evolution and development, involves cellular mechanisms that are typically associated with disease or injury.