The theory of an inflammation pathway stands for viral or inflammatory triggering factors leading to the clonal expansion of CD8
+ T cells and T cell-mediated cytotoxicity, which ultimately result in damage or death of muscle fibres[
33]. This theory is supported by the increased occurrence of sIBM in the presence of autoimmune disorders and HIV and HTLV-1 infection[
34]. Degenerative changes and endoplasmic reticulum (ER) stress are considered as secondary mechanisms induced by increased intracellular cytokines and chemokines[
33]. The degree of mitochondrial changes and muscle atrophy were suggested to be strongly correlated with the severity of inflammation in a recent study[
35].
However, sIBM is poorly responsive to even vigorous immunosuppression. Even where there is histopathological evidence that inflammation was reduced, this was not accompanied by clinical improvement. Therefore, some investigators are supporting a degenerative hypothesis over inflammation as the primary pathogenesis of sIBM. The identification of aberrant protein aggregates in sIBM vacuolated muscle fibres has shown the remarkable parallels of those features in brain tissue of Alzheimer’s disease (AD) and Parkinson’s disease with Lewy bodies. This theory suggests that inflammation is secondary to the degeneration-associated processes in sIBM muscle fibres[
36] including: 1) multiple protein aggregates[
37], 2) abnormal accumulation of lipoprotein receptors and free cholesterol[
38], 3) oxidative stress[
39], 4) inhibition of the ‘ubiquitin-proteasome system’ (UPS)[
40], 5) endoplasmic reticulum stress[
41], and 6) impaired autophagy-lysosome pathway[
41]. Furthermore, myonuclear disintegration is also involved in the pathogenic process leading to the formation of rimmed vacuoles. This results in a severe consequence that is a progressive reduction of the number of myonuclei and further progressive muscle atrophy[
42].
Despite sIBM not being an inherited Mendelian disease, multiple genetic risk factors are being shown likely to play important roles in the development and progression of sIBM. A list of possible susceptibility genes that could be important candidate genes for understanding the pathogenesis of sIBM is shown in Table
3. Furthermore, the prevalence of sIBM differs between different ethnic populations. This is likely due to differences in genetic makeup of different racial/ethnic groups and differences in the environmental factors of different geographical regions[
29].
Table 3
Summary of possible susceptibility genes for sIBM based on current research and discussed in this review
Immune-associated genes | MHC region[ 43]; NT5C1A gene[ 44]. |
Degenerative-associated genes | APP gene[ 45]; PSEN gene[ 46]; DYSF gene[ 47]; APOE gene[ 48]; MAPT gene[ 49]; PRNP gene[ 50]; SERPINA3 gene[ 51]; TARDBP gene[ 52]; hnRNPA1 and hnRNPA2B1 genes[ 53]; C9orf72[ 54] . |
mtDNA-associated sequences/genes | mtDNA deletions[ 55]; Nuclear coding mitochondrial genes: TYMP, SLC25A4, C10orf2, POLG1, and TOMM40 gene[ 16, 56]. |
Mitochondrial DNA abnormalities (mtDNA deletions) and sIBM
Mitochondrial abnormalities are another important pathological feature in sIBM muscle biopsies, consisting of ragged-red fibres and mostly showing enzyme histochemical deficiency of COX activity. These changes are more prevalent in sIBM than in polymyositis, dermatomyositis and normal ageing muscle fibres[
102]. It is therefore of great interest to investigate another group of susceptibility factors – mitochondrial DNA (mtDNA). An accumulation of mtDNA molecules with large-scale deletions was found in many COX-deficient ragged-red fibres of sIBM patients (e.g.[
103]), with multiple different deletions in different muscle fibres but usually one predominant type of mtDNA deletion present in each COX-deficient fibre[
55,
104]. Thirty-three different deletions were identified by sequencing four patients with sIBM. The majority of mtDNA deletion breakpoints identified in sIBM muscle fibres span from the region of nt8029-8032 to the region of nt16066-16078[
55] which are similar to those found in normal ageing and in autosomal dominant progressive external ophthalmoplegia (adPEO). These indicate that there may be a shared mechanism for the generation of mtDNA deletions in normal ageing, sIBM and adPEO. AdPEO and other hereditary disorders with multiple mtDNA deletions have been found associated with mutations in some nuclear genes, such as thymidine phosphorylase gene (
TYMP, previously known as
ECGF1), solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator) member 4 gene (
SLC25A4, previously known as
ANT1), chromosome 10 open reading frame 2 (
C10orf2) and polymerase gamma 1 (
POLG1), which are important for mtDNA maintenance and replication[
16]. Putative defects in these nuclear genes may directly or indirectly affect sIBM muscle. Notwithstanding no mutations in these genes were identified in sIBM cases, there is not enough evidence to exclude these genes as possible candidates. The reason for the accumulation of mtDNA deletions in sIBM muscle fibres is still unclear and no correlation between the presence of deletions and gender, age, or the main clinical features has been found so far[
16,
104]. But similar to the normal ageing muscle, mtDNA mutations in sIBM may be involved in the muscle atrophy and weakness.
In addition to mtDNA deletions, mutations at mtDNA nucleotide positions 3192, 3196, 3397 and 4336, which are associated with late-onset AD, are possible risk factors for sIBM. In sIBM cases only the frequency of the common 16311C variant has been found more frequent than in AD and controls, but these differences were not statistically significant[
105]. Interestingly, all the patients with 16311C variant were
HLA-DR3 positive[
105], suggesting that there might be some interaction between this variant and
HLA-DR3, which is in a genomic region strongly associated with sIBM. Further studies are required to investigate whether this variant plays a pathogenic role in sIBM and/or its possible interaction with other genetic factors.
Recently a gene called ‘Translocase of Outer Mitochondrial Membrane 40’ (
TOMM40) which is adjacent to and in linkage disequilibrium with the
APOE locus on chromosome 19, has been implicated in AD[
106].
TOMM40 encodes an outer mitochondrial membrane translocase facilitating the transport of unfolded proteins such as amyloid-β from the cytosol into the mitochondrial intermembrane space[
107]. A polyT repeat, an intronic polymorphism (rs10524523), in the
TOMM40 gene together with the
APOE genotypes has been shown to influence disease susceptibility of AD[
108]. It has been reported that carriers of the
APOE ϵ3 allele with a very long (VL) polyT repeat alleles in
TOMM40 had reduced risk of sIBM compared to controls, and this was also associated with a later age at onset of symptoms[
56]. The rs10524523 may modulate expression levels of
TOMM40 and/or
APOE to influence disease susceptibility. This also comes to a hypothesis that genetic variants of
TOMM40 could be associated with altered mitochondrial pore function and transport of proteins into mitochondria. This could result in energy metabolism changes and increased reactive oxygen species formation, further contributing to the impairment in mitochondria and degeneration in muscle fibres[
56].