Investigation of splicing of LMNA in sporadic inclusion body myositis (S-IBM) and ageing musclr, and a reappraisal of the MCK-ABPP mouse as a model of S-IBM

[Truncated] Sporadic inclusion body myositis (s-IBM) is the most common inflammatory myopathy in older people. It is characterised clinically by a selective pattern of weakness of the quadriceps femoris and finger flexor muscles and a poor response to immune therapies, and histologically by muscle inflammation and degenerative changes in muscle fibres including rimmed vacuoles and congophilic inclusions. The pathogenesis of s-IBM remains elusive but is known to include CD8+ T cell mediated cytotoxicity, humoral-driven autoimmunity, intracellular aggregation of amyloid β (Aβ) and other proteins, mitochondrial abnormalities, and increased muscle oxidative stress. Thus far, there has been no evidence to support any one of these abnormalities being the primary cause of s-IBM. The numbers of cytochrome C oxidase deficient muscle fibres are greater than expected for age in s-IBM muscle suggesting that the aging process may be accelerated. The occurrence of nuclear abnormalities and the localisation of the nuclear envelope proteins lamin A/C within the rimmed vacuoles have led to the hypothesis of a nuclear defect in s-IBM. Mutations in the lamin A/C (LMNA) gene can activate a cryptic splice site and lead to accumulation of a truncated lamin A isoform progerin (LMNA Δ150) and are associated with the premature ageing disease Hutchinson-Gilford progeria syndrome (HGPS).
This thesis has investigated the implications of lamin A and its mis-splicing isoform progerin in the accelerated ageing seen in s-IBM and in normal skeletal muscle ageing. It also employed antisense oligonucleotides (AOs) targeting the LMNA pre-mRNA to induce overexpression of progerin in human myogenic cells to evaluate whether it is an appropriate in vitro model of accelerated muscle ageing. In addition, it has investigated the histological, immunohistochemical and ultrastructural changes in skeletal muscles in a new lineage of the MCK-AβPP transgenic mouse and re-evaluated its suitability as an animal model for s-IBM. Finally, the thesis reviews (1) the regulation of the transcription and splicing of LMNA, (2) a subgroup of laminopathies that are caused by mis-splicing of LMNA and (3) the use of AOs to modulate LMNA splicing.