STAYING YOUNG IN OLD AGE: AN INTEGRATIVE APPROACH BASED ON NANOMEDICINE TO REDUCE SKELETAL MUSCLE IMPAIRMENT IN THE ELDERLY

Sarcopenia, a progressive and generalized loss of muscle mass and function, is the main cause of frailty in older people and still lacks an efficient drug therapy. It is rapidly becoming a major health and social problem since the percentage of elderly people is rapidly increasing. Sarcopenic muscle is characterized by chronic inflammation and malfunction of mitochondrial metabolism causing oxidative stress. Here we propose to achieve an integrative and presumable synergic action against sarcopenia by combining Palmitoylethanolamide (PEA), an endocannabinoid-like molecule with an anti-inflammatory effect, with Trimetazidine (TMZ), a metabolic reprogramming agent with a proved ability to increase muscle strength in aged mice. The overall innovative objective of our proposal is to apply nanomedicine principles to obtain nano-drug delivery systems (NPs) to co-deliver the drugs and control their temporal and spatial release, thus reducing the frequency of administration, meet compliance of patients, minimize side effects, and reduce health care costs. Two kinds of NPs will be investigated: solid lipid nanoparticles (SLN), nanocarriers with a solid lipid core made up of biocompatible ingredients, and nanoparticles based on poly(lactide-co-glicolide) polymer (PLGA-NPs), a nanosystem with high affinity for muscle made of a FDA approved polymer. Our project also aims at enhancing the effects of these molecules by homing them directly into skeletal muscle by means of functionalized NPs. The project involves two research units, RU A and RU B, with complementary skills. RU A is directed by Prof. Eliana Leo (UniMoRE) with skills relating to nanomedicine, NPs characterization (Dr. Cecilia Rustichelli), and molecular biology of muscle cells (Dr. Susanna Molinari). RU B directed by Prof. Elisabetta Ferraro (UniPi) has deep biological expertise in handling aged mice and analysing sarcopenic skeletal muscles. NPs produced and characterized by RU A will be evaluated in vitro on bi-dimensional and three-dimensional cultured muscle cells (the latter in collaboration with Prof. Cesare Gargioli, Univ. Tor Vergata, Rome). Selected NPs will be evaluated by RU B for skeletal muscle atrophy and oxidative stress on a mouse model of aging. The in-depth analysis of bioenergetic profile will be performed in collaboration with Prof. Filippo Santorelli (IRCCS Stella Maris, Pisa), while the collaboration with Dr. Vincent Gache (INSERM, Lyon) will allow analysis of the neuromuscular junction (NMJ). We expect that targeting both TMZ and PEA to skeletal muscle by NPs might represent a disruptive approach to treat sarcopenia. In addition to translational results, we expect knowledge advances in elucidating the complex molecular mechanisms of the disease, a field still in its infancy.