Dottorato in GENETICA E BIOLOGIA MOLECOLARE

Titolo della tesi: Investigating the role of cyclin D3 in skeletal muscle development and remodelling in pathophysiological conditions

The mitogen-induced D-type cyclins (D1, D2 and D3) are regulatory subunits of the cyclin-dependent kinases CDK4 and CDK6 that drive progression through the G1 phase of the cell cycle. Moreover, by now it’s clear that D-type cyclins can play non-canonical roles in a tissue-specific manner. In skeletal muscle, cyclin D3 regulates the muscle fiber type phenotype by repressing the slow/oxidative fiber-specific gene expression program through multiple mechanisms, including inhibition of MEF2 and NFAT transcriptional activity. Starting from this knowledge, here we show novel functions of cyclin D3 in the regulation of adult muscle plasticity in response to physiological external stimuli and pathologic conditions. By subjecting mice lacking cyclin D3 to voluntary wheel running and food deprivation, we observed that cyclinD3(−/−) skeletal muscle can respond efficiently to both stimuli. In particular, cyclinD3(-/-) mice displayed a more pronounced fast-to-slow fiber type shift during the voluntary endurance exercise and a slightly increased response to fasting, probably due to an up-regulation of the phosphorylated active form of the AMP-dependent protein kinase (AMPK). Furthermore, by using the mdx mouse model of Duchenne-Muscular Dystrophy (DMD) interbred with cyclinD3(-/-) mice (double mutant: mdx/D3(-/-)), we found that the constitutive ablation of cyclin D3 ameliorates the progression of the pathology, attenuating chronic muscle necrosis and degeneration compensated by regeneration. Our data suggest that the beneficial effects of the absence of cyclin D3 in a mdx mouse model are in part due to stimulation of fast-to-slow and glycolytic-to-oxidative shift of the dystrophic skeletal muscle phenotype.