Characterizing Neuromuscular Degeneration in Limb-girdle Muscular Dystrophy Type 2G from Titin Cap Mutation in Mouse Models


Pre-Clinical Research

Poster Number: T360


Aria Ma, The Jackson Laboratory, Sarah Holbrook, The Jackson Laboratory, Jennifer Stauffer, The Jackson Laboratory, Gregory Cox, PhD, The Jackson Laboratory

Titin cap (TCAP) encodes for telethonin, a protein necessary in sarcomere assembly in muscle myofibrils. Deleterious mutations in TCAP result in total deficiency of telethonin in the muscle, causing human limb-girdle muscular dystrophy type 2G (LGMD2G). This adult-onset autosomal recessive myopathy is characterized by progressive muscle weakness and wasting in the upper and lower limbs, and mild deterioration of the respiration system. The impact on different muscle fibers in affected muscle groups as neuromuscular degeneration progresses is currently unknown. The mouse model of a patient derived recessive Tcap mutation is used in the Cox lab at The Jackson Laboratory where we generated a mouse model replicating its parallel human mutation. This study examined the hindlimb tissue from 8-month, 12-month, and 24-month old mice to characterize the neuromuscular degeneration progression and investigate associating phenotypes with exhibiting fast and slow twitch muscles. Through manually examining four key muscles (tibialis anterior, peroneus longus, soleus, and medial gastrocnemius) in FIJI, a variety of muscles are represented to understand how the mutation affects muscle impairment. Progression of this myogenic disease is recorded through the analysis of the muscle fiber area of the four key muscles, as well as instances of central nucleation and unknown aggregate formation. The results show that progression of disease affects slow and fast twitch muscles differently with instances of aggregates and central nuclei differing for both at different time points. Higher instances of central nucleation may be the repair mechanisms at work as the muscle deteriorates. Further investigation into aggregate material properties and specific response mechanisms of fast and slow twitch muscle fibers is needed to understand how progression of LGMD2G affects human symptoms.