Frailty is a clinical state of increased vulnerability to poor resolution of homoeostasis after a stressor event. Sarcopenia, the decline in skeletal muscle mass and function that accompanies aging, is one of the major contributor of frailty, and it is associated to poorer quality of life, increased risk of falls and hospitalization. The molecular mechanisms underlying sarcopenia is elusive and the development of optimal therapeutic interventions remains obscure. Elucidating frailty etiology in different individuals is therefore pivotal in order to identify functional clinical parameters, new markers for frailty prevention as well as novel targets for treatment.
Obiettivi Because of the well-described role of the BRD4 inhibitor JQ1 in attenuating inflammation and based on our preliminary data in two models of muscle wasting, we propose to test the efficacy of the small inhibitor JQ1 in delaying sarcopenia in old mice, elucidating its impact in inflammation, autophagy and regeneration. We will study the genome-wide occupancy of the bromodomain protein BRD4 in aged versus young mice. In addition, we will focus our attention on the involvement of miRs in modulating inflammation, autophagy and regeneration, in young versus old mice.
Strategia We will use a mouse model of physiological aging to uncover molecular mechanisms underlying alterations of inflammation, autophagy and regeneration in the aging skeletal muscle. Additionally, we will clinically evaluate sarcopenia in a cohort of young/old volunteers and correlate it with modulations of these three key processes in humans biopsies.
Risultati attesi If successful, this proposal will elucidate novel epigenetic mechanisms underlying inflammation, regeneration and autophagy during sarcopenia, shedding new light on the role of miRs and of the BRD4 protein in skeletal muscle aging. Importantly, we expect to assess the efficacy of the BRD4 small inhibitor JQ1 in preventing age-related muscle wasting. The experimental model will be challenged with findings on inflammation, autophagy, regeneration in a cohort of young and old volunteers.