Role of cyclin D3 in the control of metabolic, contractile and biochemical properties of skeletal muscle fibers in the mouse model of Duchenne Muscular Dystrophy

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, there is increasing evidence that D-type cyclins may also perform cell cycle-independent functions 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, in my thesis work, novel functions of cyclin D3 in the regulation of adult muscle plasticity in the pathologic condition of muscular dystrophy will be shown, by using the mdx mouse model of Duchenne-Muscular Dystrophy (DMD) interbred with cyclinD3(-/-) mice (double mutant: mdx/D3(-/-)). The results demonstrate that the constitutive ablation of cyclin D3 ameliorates the progression of the pathology (in 5 weeks, 2- and 5-month-old mice), attenuating chronic muscle necrosis and degeneration compensated by regeneration. Furthermore, the data suggest that the beneficial effects of the absence of cyclin D3 in the mdx mouse model are in part due to stimulation of fast-to-slow and glycolytic-to-oxidative shifts of the dystrophic skeletal muscle phenotype. Moreover, 5-month-old mdx/D3(-/-) mice show improved running performance and a lower rate of muscle degeneration in response to contraction-induced injury. Interestingly, under post-exercise conditions, mdx/D3(-/-) mice display a burst of regeneration, suggesting that slowing down the degeneration/regeneration process of dystrophic muscle in the early phase of the disease can prevent the rapid depletion of the skeletal muscle stem cell pool.