EFFICACY OF INNOVATIVE PHARMACOLOGICAL INTERVENTIONS TO COUNTERACT PHYSICAL DECLINE

Physical decline is one of the main biological and clinical challenges of adulthood and the elderly population. It leads to a loss of functional autonomy and a reduced quality of life, as well as an increased risk of disability and hospitalisation. This process results from the interaction between biological ageing, chronic pathological conditions, environmental and behavioural factors, and manifests as a progressive deterioration in musculoskeletal function. Skeletal muscle plays a central role in maintaining systemic homeostasis and contributes to locomotion, energy metabolism, and endocrine signalling. Muscle mass and function are regulated by complex molecular and cellular mechanisms. During ageing and in the presence of pathological conditions, alterations to these systems lead to the activation of catabolic pathways and progressive loss of structural and functional integrity. This results in muscle atrophy, which is characterised by a reduction in muscle mass, contractile strength, and physical performance. In this pathophysiological context, sarcopenia is a specific type of age-related muscle atrophy. While there are currently no pharmacological treatments available, nutritional interventions and physical activity are the most effective therapeutic strategies. Sarcopenia is also frequently associated with comorbidities (e.g., kidney fibrosis) that worsen the clinical condition. Although various screening strategies and diagnostic criteria based on the assessment of muscle function and mass have been proposed, many countries have yet to develop specific diagnostic tools and therapeutic protocols. Identifying new predictive biomarkers could enable early diagnosis and facilitate the development of personalised therapeutic approaches. Based on the available literature, this thesis mainly focuses on identifying potential plasma biomarkers of sarcopenia in the elderly population. This study forms part of the IN-TeMPO project (Spoke 8; ClinicalTrials.gov ID: NCT06248723), which is integral to the national AGE-IT project promoting healthy and active ageing through a multidisciplinary and translational approach. At the same time, in a preclinical setting, nutritional and pharmacological intervention strategies were evaluated in mouse models of physiological ageing. Specifically, the effects of branched-chain amino acid supplements, which have previously been shown to enhance muscle strength and mass in this model, were investigated. Particular attention was given to their role in restoring intracellular calcium homeostasis and their potential anti-fibrotic effect on the kidneys. Additionally, the therapeutic potential of the growth hormone secretagogue JMV2894 was evaluated in the D2.B10-Dmdmdx/J (D2-mdx) mouse model, which is characterised by a profibrotic genetic background and a severe dystrophic phenotype . The effects of treatment were analysed using morphological and molecular endpoints in vivo and ex vivo. Overall, this thesis aims to advance translational strategies for the early diagnosis and treatment of muscle decline associated with aging and neuromuscular diseases.