Satellite cells are mitotically quiescent myogenic stem cells resident beneath the basal lamina surrounding adult muscle myofibers. In response to injury, multiple extrinsic signals drive the entry of satellite cells into the cell cycle and then to proliferation, differentiation, and self-renewal of their downstream progeny. Because satellite cells must endure for a lifetime, their cell cycle activity must be carefully controlled to coordinate proliferative expansion and self-renewal with the onset of the differentiation program. In this study, we find that cyclin D3, a member of the family of mitogen-activated D-type cyclins, is critically required for proper developmental progression of myogenic progenitors. Using a cyclin D3-knockout mouse we determined that cyclin D3 deficiency leads to reduced myofiber size and impaired establishment of the satellite cell population within the adult muscle. Cyclin D3-null myogenic progenitors, studied ex vivo on isolated myofibers and in vitro, displayed impaired cell cycle progression, increased differentiation potential, and reduced self-renewal capability. Similarly, silencing of cyclin D3 in C2 myoblasts caused anticipated exit from the cell cycle and precocious onset of terminal differentiation. After induced muscle damage, cyclin D3-null myogenic progenitors exhibited proliferation deficits, a precocious ability to form newly generated myofibers and a reduced capability to repopulate the satellite cell niche at later stages of the regeneration process. These results indicate that cyclin D3 plays a cell-autonomous and nonredundant function in regulating the dynamic balance between proliferation, differentiation, and self-renewal that normally establishes an appropriate pool size of adult satellite cells.

HIV-infected patients have a significantly greater risk of cardiovascular disease. Several markers including osteoprotegerin have been shown to be involved in the development and progression of atherosclerosis. We investigated the relationship between T-cell phenotype, osteoprotegerin, and atherosclerosis evaluated by carotid intima-media thickness (c-IMT) in 94 HIV+ patients on suppressive antiretroviral therapy with Framingham score <10%. As for the control group, 24 HIV-negative subjects were enrolled. c-IMT was assessed by ultrasound. CD4+/CD8+ T-cell activation (CD38+ HLADR+) and senescence (CD57+ CD28−) were measured by flow cytometry. IL-6 and OPG levels were measured by ELISA kit. c-IMT was higher in HIV+ than in controls. Among HIV+ patients, 44.7% had pathological c-IMT (≥0.9 mm). CD8+ T-cell activation and senescence and OPG plasma levels were higher in HIV+ patients than in controls. Subjects with pathological c-IMT exhibited higher CD8+ immune activation and immunosenescence and OPG levels than subjects with normal c-IMT. Multivariate analysis showed that age, CD8+ CD38+ HLADR+, and CD8+ CD28− CD57+ were independently associated with pathological c-IMT. Several factors have been implicated in the pathogenesis of atherosclerosis in HIV patients. Immune activation and immunosenescence of CD8+ T cell together with OPG plasma levels might be associated with the development and progression of early atherosclerosis, even in the case of viral suppression.