The Inhibition of Apoptosis in Myositis and in Normal Muscle Cells

Abstract

The mechanism of injury and death of muscle cells in the inflammatory myopathies (dermatomyositis, polymyositis, and inclusion body myositis) remains obscure. We and others have not detected apoptosis in the muscle biopsies from patients with myositis despite clear evidence of cell damage and loss. We provide evidence in this study that Fas ligand (FasL) as well as Fas is present on muscle cells and inflammatory cells in myositis biopsies: Fas is present on most muscle cells and lymphocytes, and FasL is present on degenerating muscle cells and many infiltrating mononuclear cells. The expression of both Fas and FasL in the inflamed tissue makes the absence of apoptosis more striking. To address the mechanisms of this resistance to classical apoptosis in muscle cells, we have investigated the expression of the antiapoptotic molecule FLICE (Fas-associated death domain-like IL-1-converting enzyme)-inhibitory protein (FLIP) in muscle biopsies of myositis patients and in cultured human skeletal muscle cells. Using laser capture microscopy, we have shown that FLIP is expressed in the muscle fibers and on infiltrating lymphocytes of myositis biopsies. Furthermore, we have shown that FLIP, but not Bcl-2, is expressed in cultured human skeletal muscle cells stimulated with proinflammatory cytokines, and inhibition of FLIP with antisense oligonucleotides promotes significant cleavage of poly(ADP-ribose) polymerase autoantigen, a sensitive indicator of apoptosis. These studies strongly suggest that the resistance of muscle to Fas-mediated apoptosis is due to the expression of FLIP in muscle cells in the inflammatory environment in myositis.

Death receptor-associated pro-apoptotic signaling in aged skeletal muscle

“…In contrast, type II cells accumulate considerably less DISC and require mitochondrial signaling to fully activate an apoptotic program. The current study as well as data from Nagaraju et al [49] suggest that skeletal muscle cells may act as type II cells, in that apoptotic signaling arising from the death receptor can include subsequent mitochondrial apoptotic signaling through Bid activation. Future studies should directly address the ability of truncated Bid to mediate messages from the death receptor to the mitochondria.…”

“…The data from the current study is consistent with this hypothesis by showing that muscles from aged rodents up-regulate the anti-apoptotic protein, FLIP. FLIP protein can attenuate apoptotic signaling downstream of death receptors by inhibiting the cleavage of procaspase-8 [46][47][48][49]. However, despite these aging-related adaptations, the up-regulation of FLIP and Bcl-2 proteins appears to be ineffective in attenuating myonuclear loss in aged muscles.…”

Apoptosis in the skeletal muscle of untreated children with juvenile dermatomyositis: Impact of duration of untreated disease

“…This system is thought to be important in regulating the immune system as mutations of Fas and FasL in humans cause autoimmune lymphoproliferative syndrome (ALPS) [25;26]. Fas receptor was previously identified both on muscle fibers and on the infiltrating mononuclear cells from patients with either polymyositis or dermatomyositis [27], and FasL was localized to muscle fibers and mononuclear cells in adults with polymyositis [13]. In our study, Fas was expressed on mononuclear cells as well as muscle fibers in the diagnostic muscle biopsy from JDM patients, which is similar to the previous observation.…”

“…Serum levels of muscle enzymes (aldolase, lactic dehydrogenase, creatine kinase, serum glutamic-oxaloacetic transaminase/aspartate aminotransferase) tend to be in the normal level with disease duration longer than 4.7 months, but the underlying mechanism for this observation is unknown [10]. Skeletal muscle fiber has been shown to upregulate Fas Ligand (FasL) and FLIP to counteract the apoptosis during inflammation [13]. Thus, longer disease duration may influence the type of apoptosis in JDM.…”

Results and long‐term followup of intravenous immunoglobulin infusions in chronic, refractory polymyositis: An open study with thirty‐five adult patients

“…In addition to the recent theory described above, several mechanisms may be proposed and associated: 1) the blockade of IgG Fc receptors on phagocytic cells by the infused IVIG, thereby preventing the removal of cells, sensitized with autoantibodies of IgG isotype, from the circulation; 2) the presence of antiidiopathic antibodies capable of suppressing autoantibody secretion in the pool of plasma donors used for IVIG production; 3) a direct effect on B and T lymphocytes; 4) the inhibition of adhesion molecules and cytokine production; and/or 5) the presence of soluble CD4, CD8, and HLA in IVIG, which modify antigen recognition by target cells. These 2 last theories are probably important, since IVIG might also provide a source of antiidiotypic antibodies directed against chemokines, HLA antigens, adhesion molecules, and especially the selectin family, and antiapoptotic molecules and metalloproteases, which are known to be involved in the pathogenesis of myositis (22,(33)(34)(35)(36)(37)(38)(39)(40).…”