
Unravelling new pathways and innovative perspectives for treating rare skeletal muscle disorders: focus on the endocannabinoid system and its interplay with the gut microbiota
Fabio Arturo Iannotti, Institute of Biomolecular Chemistry, National Research Council of Italy
Host: Natércia Teixeira, UCIBIO Porto
ZOOM link: https://ucibio.pt/l/GuestSeminars
ID da reunião: 865 7786 0516
Senha: 805165
Abstract:
Skeletal muscle dystrophies comprise a well-known group of hereditary disorders associated with a devastating deterioration of muscle tissues. Among them, Duchenne’s muscular dystrophy (DMD) is the most frequent form affecting about 1 in 3500 live male births. The disease is caused by mutations in the gene encoding for the structural protein dystrophin. In healthy muscles, dystrophin is important to physically to connect the cytoskeleton with the sarcolemma. Therefore, the absence or reduced expression of dystrophin causes skeletal muscle damage, a condition that is further aggravated by ensuing inflammation, impairment of autophagy, fibrosis and tissue necrosis, leading to irreversible tissue degeneration. Unfortunately, a cure for DMD is still not available, although experimental therapies have made astonishing advances over the years. Hence, the use of anti-inflammatory drugs including steroids remains the mainstay of palliative care. Despite the promising use of endocannabinoids or plant cannabinoids as complementary and/or alternative medicines, to date, their potential use in skeletal muscle disorders is still largely unexplored. Only recently, we demonstrated that: (i) in both murine and human skeletal muscle cell precursors (myoblasts), 2-AG promotes proliferation and inhibits differentiation to mature muscle cells (myotubes); (ii) 2-AG negatively controls skeletal muscle formation in vivo; (iii) there is an increased activity of the ECS in both murine and human skeletal muscles affected by DMD; and (iv) the pharmacological inhibition of the endocannabinoid CB1 receptor significantly enhances satellite cell and myoblast to myotube differentiation, delays locomotor impairment in dystrophic mice and reduces their muscle inflammation. Intriguingly, the ECS activity could be under the influence of the gut microbiota and vice versa. However, whether the ECS could represent an additional signalling mechanism through which the gut microbiota interacts with skeletal muscle remains to date completely unexplored. Our work reveals a mechanism through which a dysfunctional gut microbiota, by causing aberrant CB1 activity, underlies part of the pathological features of a mouse model of DMD, thus contributing to identifying novel mechanisms and therapeutic strategies for rare and untreatable skeletal muscle disorders.
Shot Bio:
Fabio Arturo Iannotti received his Bachelor's Degree in Biotechnology (Medical curriculum) at the University of Naples "Federico II" in 2006 with the highest score. In 2010, Dr Iannotti graduated with a PhD in Neuroscience from the same University. During this time, he studied the expression and role of voltage-gated Kv7 K+ channels during skeletal muscle formation as well as pathological conditions. The role of Kv7 channels was also investigated in infantile forms of drug-resistant epilepsy (BFNS). Part of this research was carried out during an internship at the University of California-Davis (USA) from 2009-2010. In 2011, he started his postdoc at the Institute of Biomolecular Chemistry (ICB)/National Council of Research (CNR), initiating pioneering studies on the role of endocannabinoids and plant-derived cannabinoids in rare untreatable skeletal muscle disorders and again in rare forms of drug-resistant epilepsy. In 2012/2013, he was a visiting researcher at the University of Reading (UK). Since 2014, he was promoted to the position of researcher at the ICB. In 2018, he was qualified as Associate Professor of Pharmacology and Molecular Biology. Dr Iannotti has published many papers on this area of research in international, peer-reviewed journals and has received awards from both national and international scientific societies for his innovative studies.
Main discoveries:
Discovery of the role of Kv7 K+ channels (in particular of Kv7.4 subunit) during skeletal muscle cell differentiation and prevention from myotoxic insults
Discovery of the role of the Endocannabinoid System in skeletal muscle formation and development
Discovery of the role of Endocannabinoid System in rare skeletal muscle disorders
Discovery of the anti-inflammatory and pro-autophagic action of CB1 receptor antagonists and/or plant-derived cannabinoids in rare skeletal muscle disorders (i.e. Duchenne Muscular Dystrophy)
Discovery of TRPV1 channels modulation by plant-derived cannabinoids in drug-resistant epilepsy
Keywords:
Endocannabinoid System (ECS), Plant-derived Cannabinoids (phytocannabinoids), Epilepsy; TRP channels; Skeletal Muscle Disorders.