Mechanotransduction at the z-disc of skeletal muscle

The importance of the transglutaminase-like protein kyphoscoliosis peptidase (KY) in skeletal muscle was discovered in a KY-deficient mouse model of hereditary kyphoscoliosis (ky/ky). The ky/ky pathology primarily affects muscles experiencing high tension, e.g., the soleus, which undergoes regeneration and shows persistent hallmarks of structural damage, including the aberrant localisation of the z-disc crosslinker Filamin C (FLNC) – a known KY interaction partner. However, muscles are globally smaller in size, and fast-twitch muscles (e.g., the extensor digitorum longus or EDL) show an inability to undergo hypertrophy in response to elevated tension. A robust function for KY has not been identified. Recently reported human cases of KY-deficient myopathy share hallmarks with the mouse pathology and underscore the value of increasing our understanding of KY and its function. Chaperone Assisted Selective Autophagy (CASA) is a tension-induced mechanism for FLNC turnover understood to be critical for muscle maintenance. This thesis hypothesises that the absence of KY disrupts CASA, thereby indicating that KY might have a role in CASA. This thesis examines CASA in the ky/ky mouse model and describes the generation and analysis of novel cellular (C2C12) and zebrafish models of KY-deficiency. These indicate that constitutive upregulation of CASA markers may be a primary hallmark of KY-deficiency. Additionally, data may indicate inefficient turnover of the CASA complex in tissues experiencing high tension. It is also shown that in vivo overexpression of recombinant KY is not sufficient to drive hypertrophy in normal mice, but may partially rescue fibre size in ky/ky mice