Senescent fibro-adipogenic progenitors are potential drivers of pathology in inclusion body myositis

Abstract

Inclusion body myositis (IBM) is unique across the spectrum of idiopathic inflammatory myopathies (IIM) due to its distinct clinical presentation and refractoriness to current treatment approaches. One explanation for this resistance may be the engagement of cell-autonomous mechanisms that sustain or promote disease progression of IBM independent of inflammatory activity. In this study, we focused on senescence of tissue-resident cells as potential driver of disease. For this purpose, we compared IBM patients to non-diseased controls and immune-mediated necrotizing myopathy patients. Histopathological analysis suggested that cellular senescence is a prominent feature of IBM, primarily affecting non-myogenic cells. In-depth analysis by single nuclei RNA sequencing allowed for the deconvolution and study of muscle-resident cell populations. Among these, we identified a specific cluster of fibro-adipogenic progenitors (FAPs) that demonstrated key hallmarks of senescence, including a pro-inflammatory secretome, expression of p21, increased β-galactosidase activity, and engagement of senescence pathways. FAP function is required for muscle cell health with changes to their phenotype potentially proving detrimental. In this respect, the transcriptomic landscape of IBM was also characterized by changes to the myogenic compartment demonstrating a pronounced loss of type 2A myofibers and a rarefication of acetylcholine receptor expressing myofibers. IBM muscle cells also engaged a specific pro-inflammatory phenotype defined by intracellular complement activity and the expression of immunogenic surface molecules. Skeletal muscle cell dysfunction may be linked to FAP senescence by a change in the collagen composition of the latter. Senescent FAPs lose collagen type XV expression, which is required to support myofibers’ structural integrity and neuromuscular junction formation in vitro. Taken together, this study demonstrates an altered phenotypical landscape of muscle-resident cells and that FAPs, and not myofibers, are the primary senescent cell type in IBM.

Effects of sporadic inclusion body myositis on skeletal muscle fibre type specific morphology and markers of regeneration and inflammation

“…Figure B ). These findings underline that the sIBM disease process not only severely affects lower limb muscle fibre morphology in accordance with the previous reports [ 12 , 13 ], but also supports the findings in a recently published study by Nelke et al, that to our knowledge, is the first to reveal that the atrophic effect of the disease appears to be highly fibre type-specific, preferentially affecting fast-contracting type 2 myofibres [ 24 ].…”

miR-27b-3p reduces muscle fibrosis during chronic skeletal muscle injury by targeting TGF-βR1/Smad pathway

“…Giuliani and colleagues noted that FAPs expressing high levels of sca-1 exhibited a stronger inclination towards adipogenic differentiation in vitro. These cells also displayed increased sensitivity to fibrotic stimuli, resulting in elevated expression of col1 and tissue inhibitor of metalloproteinase1 (TIMP1) [ 64 ]. Malecova et al identified two distinct FAPs subpopulations characterized by the expression of TEK receptor tyrosine kinase (Tie2) and vascular cell adhesion molecule 1 (Vcam1).…”

Recombinant Acetylcholine Receptor Immunization Induces a Robust Model of Experimental Autoimmune Myasthenia Gravis in Mice

“…The biopsies were blinded for quantification with the group not possible to identify from the label. The scoring was performed in randomly distributed 10 high-power fields (HPF, based on the microscope used and the respective oculars ≙ 0.16 mm 2 ), as previously described [ 12 ].…”