Duchenne muscular dystrophy (DMD) is a X-linked neuromuscular disorder characterised by progressive muscle degeneration leading to cardiorespiratory failure linked to the loss of dystrophin. We performed a comprehensive comparative myopathologic analysis between 21 DMD boys muscle biopsies divided by age classes,1-2 n= 5, 3-4 n=4, 5-6 n=4, 7-8 n=3 and >8 n=5 years old, aged matched control biopsies, mdx4cv mice, and R-DMDdel52 rats (Taglietti et al., in preparation) analysed at 3, 6, 12 and 17 months. Histopathologic markers including nuclear internalization, fibro-fatty substitution, necrosis, inflammation, and morphometry were assessed in human biopsies and rodents. Muscle stem cells number, regeneration, and senescence markers were evaluated with Pax7, eMyHC, p16, p21 and yH2AXimmunohistochemistry. We identified progressive reduced regenerative capacities in DMD boys as well as in animal models over the time. More importantly DMD patients and rat DMD preclinical model, showed a progressive functional exhaustion of the muscle stem cells pool with an early acquisition of senescence traits. In contrast, mdx4cv mice, muscle stem cells did not acquire senescence markers, possibly explaining the milder phenotype of this model. This work discloses the presence of a senescence phenotype in DMD muscle stem cells and stresses the importance of comparative myopathologic analyses for both pathophysiologic dissection and identification of precise histopathologic readouts/outcome measures in view of novel therapeutic approaches.

Myopathologic readouts identification in dystrophinopathies trough comparative analyses of human and animal models muscles / Nastasia Cardone. - (2022).

Myopathologic readouts identification in dystrophinopathies trough comparative analyses of human and animal models muscles

Nastasia Cardone
2022

Abstract

Duchenne muscular dystrophy (DMD) is a X-linked neuromuscular disorder characterised by progressive muscle degeneration leading to cardiorespiratory failure linked to the loss of dystrophin. We performed a comprehensive comparative myopathologic analysis between 21 DMD boys muscle biopsies divided by age classes,1-2 n= 5, 3-4 n=4, 5-6 n=4, 7-8 n=3 and >8 n=5 years old, aged matched control biopsies, mdx4cv mice, and R-DMDdel52 rats (Taglietti et al., in preparation) analysed at 3, 6, 12 and 17 months. Histopathologic markers including nuclear internalization, fibro-fatty substitution, necrosis, inflammation, and morphometry were assessed in human biopsies and rodents. Muscle stem cells number, regeneration, and senescence markers were evaluated with Pax7, eMyHC, p16, p21 and yH2AXimmunohistochemistry. We identified progressive reduced regenerative capacities in DMD boys as well as in animal models over the time. More importantly DMD patients and rat DMD preclinical model, showed a progressive functional exhaustion of the muscle stem cells pool with an early acquisition of senescence traits. In contrast, mdx4cv mice, muscle stem cells did not acquire senescence markers, possibly explaining the milder phenotype of this model. This work discloses the presence of a senescence phenotype in DMD muscle stem cells and stresses the importance of comparative myopathologic analyses for both pathophysiologic dissection and identification of precise histopathologic readouts/outcome measures in view of novel therapeutic approaches.
Alessandro Malandrini
Nastasia Cardone
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2158/1279908
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