Vaccaro, Emanuela (2024) The pathogenetic role of coronavirus and post-translational modifications in neuromuscular diseases. [Tesi di dottorato]

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Abstract

Muscle pathology is a broad field characterized by skeletal muscle structure or function diseases. These disorders may result from genetic, inflammatory, metabolic, toxic, or other systemic causes. The thesis examines two categories of muscle diseases: inflammatory myopathies and neurogenic diseases. Inflammatory myopathies (IM) are a heterogeneous group of acquired muscle disorders that are underestimated in human and veterinary medicine. They can be associated with bacterial, parasitic, and viral infections, but they are still unknown in many cases. Most inflammatory myopathies are considered autoimmune disorders in which the immune system inappropriately targets skeletal muscle. In animals, IM has been described in association with several infectious diseases, such as leishmaniasis in dogs, piroplasmosis in horses, feline immunodeficiency virus (FIV) in cats, human immunodeficiency virus (HIV) and Coronavirus (SARS-CoV 2) in humans. The morphological and molecular features of these IMs support an autoimmune pathogenesis, as circulating anti-muscle autoantibodies have been found in each of these infectious diseases. Therefore, the first chapter of this doctoral dissertation aims to investigate the presence of inflammatory infiltrates and circulating autoantibodies against to skeletal muscle in feline Coronavirus (FCoV)-positive cats. In addition, we evaluated a preexisting cross-immunity between FCoV and SARS-CoV-2. The impact of neural activity on skeletal muscle becomes evident when there is a rapid and substantial muscular deterioration resulting from disruption or lack of neuronal input. For instance, in cases of injury, severance, or compression of a nerve, atrophy sets in at a notably accelerated pace compared to other factors such as immobilization, cachexia, malnutrition, aging, and dystrophies. Dogs suffering from neurogenic atrophy endure a diminished quality of life because of sensory and motor impairments, including coordination abilities, twitching, and decreased ability to sense pain, touch, or temperature changes. Tubulin posttranslational modifications (PTMs) have emerged as important regulators of the neuronal microtubule cytoskeleton. In particular, the PTM D2, the only irreversible PTM and a marker of hyper stable microtubules is implicated in neurodegeneration, as well as axon regeneration failure. In the second chapter of the thesis, we explored whether PTMs are involved in canine neurogenic muscular atrophy.

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