Spinal muscular atrophy with respiratory distress type 1 (
SMARD1) is an autosomal recessive disease that causes distal limb
muscle atrophy, due to motor neuron degeneration. Similar to other
motor neuron diseases,
SMARD1 shows differential vulnerability to
denervation in various muscle groups, which is recapitulated in the nmd mouse, a model of
SMARD1. In multiple
neurodegenerative disease models, transcriptomic analysis has identified differentially expressed genes between vulnerable motor neuron populations, but the mechanism leading to susceptibility is largely unknown. To investigate if
denervation vulnerability is linked to intrinsic muscle properties, we analyzed muscle fiber-type composition in muscles from motor units that show different degrees of
denervation in nmd mice: gastrocnemius, tibialis anterior (TA), and extensor digitorum longus (EDL). Our results revealed that
denervation vulnerability correlated with
atrophy and loss of MyHC-IIb and MyHC-IIx muscle fiber types. Interestingly, increased vulnerability also correlated with an increased abundance of MyHC-I and MyHC-IIa muscle fibers. These results indicated that MyHC-IIx muscle fibers are the most vulnerable to
denervation, followed by MyHC-IIb muscle fibers. Moreover, our data indicate that type MyHC-IIa and MyHC-IIb muscle fibers show resistance to
denervation and compensate for the loss of MyHC-IIx and MyHC-IIb muscle fibers in the most vulnerable muscles. Taken together these results provide a basis for the selective vulnerability to
denervation of specific muscles in nmd mice and identifies new targets for potential therapeutic intervention.