Endomysial Fibrosis in Duchenne Muscular Dystrophy: A Marker of Poor Outcome Associated With Macrophage Alternative Activation

TLDR

Patients with Duchenne muscular dystrophy exhibit wide variability in motor function, yet the underlying pathogenic mechanisms remain unclear. The authors performed multiparametric histologic analysis of quadriceps biopsies from 25 steroid‑free DMD patients, measuring myofiber size, hypercontracted fibers, necrosis, fibrosis, and fatty degeneration, and correlated these features with 13 clinical outcomes over a mean follow‑up of more than 10 years. The study found no residual dystrophin, and that endomysial fibrosis—linked to increased CD206+ macrophages and decreased satellite cells—was the sole histologic marker that strongly predicted poorer motor function over 10 years, independent of genotype, underscoring the therapeutic potential of antifibrotic strategies targeting macrophage‑mediated fibrosis.

Abstract

There is considerable interindividual variability in motor function among patients with Duchenne muscular dystrophy (DMD); moreover, pathogenetic mechanisms of motor dysfunction in DMD are not understood. Using multiparametric analysis, we correlated initial histologic alterations in quadriceps muscle biopsies from 25 steroid therapy-free patients with DMD with 13 relevant clinical features assessed by a single clinical team during a long-term period (mean, >10 years). There was no residual muscle dystrophin by immunohistochemistry and Western blot analysis in the biopsies. Myofiber size, hypercontracted fibers, necrotic/basophilic fibers, endomysial and perimysial fibrosis, and fatty degeneration were assessed by morphometry. Endomysial fibrosis was the only myopathologic parameter that significantly correlated with poor motor outcome as assessed by quadriceps muscle strength, manual muscle testing of upper and lower limbs at 10 years, and age at ambulation loss (all p<0.002). Motor outcome and fibrosis did not correlate with genotype. Myofibers exhibited oxidative stress-induced protein alterations and became separated from capillaries by fibrosis that was associated with both increase of CD206+ alternatively activated macrophages and a relative decrease of CD56+ satellite cells (both p<0.0001). This study provides a strong rationale for antifibrotic therapeutic strategies in DMD and supports the view that alternatively activated macrophages that are known to inhibit myogenesis while promoting cellular collagen production play a key role in myofibrosis.