Il co-attivatore trascrizionale PGC-1α come modulatore dell'accumulo degli adipociti durante la rigenerazione del muscolo scheletrico.

The muscular tissue is the most plastic and abundant tissue in the human body. One type of muscle in our body is the skeletal muscle. Skeletal muscles are associated with the skeleton and are involved in the voluntary movements of the body; indeed their main functions are to maintain the posture and to produce movement. During life, these muscles are frequently subject to damage; for this reason, they have a great ability to heal themselves. However, in muscle diseases, this ability is altered and ectopic adipocytes start to accumulate in the muscle provoking weakness and loss of muscle functions. The most common disorders, which alter muscle normal functions, are sarcopenia, cachexia and muscle dystrophies such as Duchenne muscular dystrophy (DMD). Sarcopenia can be defined as the loss of muscle mass and force associated with aging, diseases, inactivity and poor nutrition. Cachexia is a complex metabolic syndrome involving loss of weight and muscle mass with or without loss of fat mass; it is present in underlying diseases such as cancer, rheumatoid arthritis and chronic infectious diseases. Muscle dystrophies are a group of lethal genetic diseases, which result in progressive atrophy of skeletal muscle. Since in these disorders the presence of dysfunctional mitochondria was reported and potentially involved also in impaired regeneration, we focused our attention on PGC-1α, given its ability to regulate genes for mitochondrial function and integrity. This project aimed to understand whether the protein PGC-1α, once overexpressed in mouse muscles (MCK promoter) could modulate adipocyte accumulation in skeletal muscle undergoing glycerol or BaCl2 injury. The data were obtained from tibialis anterior (TA) muscles via immunofluorescence, histological analyses and RT-qPCR on adipocyte genes at the level of skeletal muscle. Before starting the experiments, we did preliminary analyses on healthy TA muscle of WT and MCK-PGC-1α mice, which showed an alteration of cell populations (CD55+ and CD142+) involved in adipocyte regulation, more precisely a decrease of CD55+ (pre-adipocyte) and an increase of CD142+ (involved in adipogenesis inhibition) in MCK-PGC-1α mice. From immunofluorescence, histological analyses and RT-qPCR, we observed that in TA muscles of young adult mice damaged with glycerol there was a significant reduction of perilipin presence, a protein binding lipid droplets of adipocytes, in the muscles of MCK-PGC-1α compared to WT mice. These results were confirmed also in middle-aged mice damaged with BaCl2. In conclusion, the reduction of adipocyte accumulation during skeletal muscle regeneration in MCK-PGC-1α mice suggests that PGC-1α, by impinging on whole muscle metabolism, could actually modulate the adipocyte deposition during regeneration of skeletal muscle. This can be the beginning of new researches about the PGC-1α effect on muscular diseases. If we obtain similar results like the ones deriving from the aforementioned studies, we could use specific diets and exercise, known PGC-1α modulators, in people affected by muscular dystrophies (DMD), sarcopenia and all disorders characterized by altered regeneration with adipocyte accumulation hoping to improve their condition. The diets and the exercise will be a supplement to the therapies usually prescribed for these diseases.