Loss of TDP-43 Splicing Repression Occurs in Myonuclei of Inclusion Body Myositis Patients.

Objective: Inclusion body myositis (IBM) is an idiopathic inflammatory myopathy with muscle pathology characterized by endomysial inflammation, rimmed vacuoles, and cytoplasmic mislocalization of transactive response DNA-binding protein 43 (TDP-43). We aimed to determine whether loss of TDP-43 splicing repression led to the production of "cryptic peptides" that could be detected in muscle biopsies as a useful biomarker for IBM.

Methods: We used an antisera against a neoepitope encoded by a TDP-43-dependent cryptic exon within hepatoma-derived growth factor-like protein 2 (HDGFL2) for immunohistochemical analysis on muscle biopsy samples of 122 patients with IBM, 181 disease controls, and 16 healthy controls without abnormal muscle pathology. In situ hybridization was also utilized to detect the localization of cryptic HDGFL2 transcripts.

Results: We found cryptic HDGFL2 peptides localized within myonuclei from muscle biopsies in 79 of 122 patients with IBM (65%), and this staining correlated with TDP-43 depletion. In contrast, cryptic HDGFL2 immunoreactivity was absent in 197 muscle biopsies from a variety of disease controls, except for 2 patients with vacuolar myopathies. Notably, we show that cryptic HDGFL2 transcripts are accompanied by the detection of cryptic HDGFL2 in muscle fibers of IBM without rimmed vacuoles and TDP-43 aggregates.

Interpretation: Together, our findings establish that loss of TDP-43 splicing repression occurs in myonuclei of IBM skeletal muscle and suggest that detection of cryptic peptides in muscle biopsies may be a useful biomarker. We suggest that a therapeutic strategy designed to restore TDP-43 function should be considered to attenuate the degeneration of skeletal muscle in this devastating disease. ANN NEUROL 2025.