"Myofibrillar myopathy (MFM) is a protein aggregate disease that causes degeneration and loss of function of skeletal muscle and sometimes cardiac muscles. The clinical signs of this disease in people are heterogenous and can include distal limb weakness, atrophy, myalgia, loss of mobility, cardiomyopathy, and respiratory compromise. Approximately half of MFM cases have heritable etiologies that range from dominant to recessive. As many as eight genes have been found to cause MFM and eight additional genes have been implicated in protein aggregate myopathies similar to MFM. Classically, MFM is a progressive late onset disease affecting adults; however, juvenile forms do occur. Currently, there is no treatment for MFM. Research into the pathogenesis and potential treatments of MFM, as a whole, can be difficult due to variation in genetic causes, potential for environmental triggers, and disparity in clinical signs among patients. As a complex disease, a naturally occurring animal model may offer a unique perspective into the mechanisms of protein aggregation in skeletal muscle and present the opportunity for translational medicine and research. MFM has been diagnosed in Warmblood (WB) horses based on the hallmark features of MFM in skeletal muscle: ectopic aggregation of a cytoskeletal protein called desmin coupled with myofibrillar disarray. WB with MFM were previously thought to have a glycogen storage disease and were placed on a recommended diet and exercise program to help manage horses with polysaccharide storage myopathies. However, recent studies found that WB diagnosed with type 2 polysaccharide storage myopathy (PSSM2) did not have elevations in skeletal muscle glycogen. This finding led to the immunohistochemical staining for desmin and MFM diagnosis. It was unknown whether a diet recommended for a glycogen storage disease was beneficial for PSSM2 and MFM WB. Furthermore, the etiopathology of WB MFM was undetermined. The overarching objective of this dissertation is to evaluate the responses of PSSM2/MFM WB to the recommended polysaccharide storage myopathy diet (PSSM) and further elucidate the etiopathology of MFM in WB by identifying candidate genes, proteins, and pathways that drive aberrant cellular responses and disease pathology. The first study used a retrospective questionnaire to determine owner perceived symptoms and responses of PSSM2/MFM WB to the PSSM diet. We determined that PSSM2/MFM WB had a decline in athletic performance and a reluctance to engage their muscles during work. Furthermore, we confirmed that PSSM2/MFM WB do not have elevations in skeletal muscle glycogen. The second study of this dissertation took a candidate gene approach to look for differential expression (DE) and coding sequence variants in 16 candidate MFM genes in MFM and non-MFM WB. Our results found there was no DE of the candidate genes and that no variants associated with the MFM disease phenotype. We next used transcriptomic and proteomic profiling to detect DE genes and proteins in MFM WB. Through pathway enrichment, we identified the Z-disc, mitochondrial complex I, and the extracellular matrix as key cellular components in MFM etiopathology. The identified new candidate genes and proteins using this multi-omic approach may serve as future diagnostic markers for MFM in WB. Overall, our results suggest MFM WB have aberrant Z-disc mechanosignaling resulting in sarcomere instability, which is further confounded by impaired redox homeostasis."--Pages ii-iii.
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