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Title: Exploring the function of IGFN1 and MLTK in skeletal muscle
Author: Li, Xiang
ISNI:       0000 0004 6060 8827
Awarding Body: University of York
Current Institution: University of York
Date of Award: 2016
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Kyphoscoliosis peptidase (KY) is a Z-disc protein essential for muscle maintenance and its absence underlies a unique type of muscular dystrophy in humans and mice (1–3). The function of KY remains uncharacterised, thus there is limited understanding about the mechanisms underlying the muscle pathology observed due to KY deficiency. Immunoglobulin-like and fibronectin type III domain containing 1 (IGFN1) was identified as a KY interaction partner which in turn interacts with MLK-like mitogen-activated protein triple kinase (MLTK) (4). This thesis aimed to develop further understanding of these interaction partners to gain novel insights into mechanisms of muscle maintenance. In this thesis, the specific interactions between IGFN1_V1 and MLTK isoforms were confirmed for the first time via immunoprecipitation and pull down assays. In addition, MLTKβ is confirmed as the primary isoform in skeletal muscle. The effects of ectopic expression of IGFN1_V1 and MTLK isoforms in mouse skeletal muscle are examined. The Z-disc localisation of these proteins is confirmed, along with nuclear localisation for IGFN1_V1. In addition, expression of IGFN1_V1 drives both ectopically and endogenously expressed MLTKβ to the nucleus. This data shows that the z-disc is the likely site for IGFN1-MLTK interactions, and suggests a function for IGFN1_V1 in the shuttling of MLTKβ to the nucleus. Overexpression of recombinant MLTKβ results in skeletal muscle fibre cross sectional area increases, and some overexpressing fibres showed disorganized myofibrils. Together with the previous finding that overexpression (5) or reduction (6) of MLTKβ causes myofibril disorganization in either cardiac or skeletal muscles, this indicates that a certain expression level of MLTKβ is important for maintaining muscle health. This thesis also describes the generation of IGFN1-deficient mouse myoblasts, which show abnormal differentiation patterns, including short myotube formation and globular differentiation bodies, indicating that IGFN1 is important for regulation of muscle myogenesis.
Supervisor: Blanco, Gonzalo Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available