Cyclin D3 critically regulates the balance between self-renewal and differentiation in skeletal muscle stem cells

Abstract

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.

Lipin1 Regulates Skeletal Muscle Differentiation through Extracellular Signal-regulated Kinase (ERK) Activation and Cyclin D Complex-regulated Cell Cycle Withdrawal

“…**, p Ͻ 0.01. those found in vivo and confirm that lipin1 is essential for effective differentiation during the early stages of myogenesis. Our data are in agreement with previous studies that ERK2 and cyclin D3 are critical for myoblast terminal differentiation (30,31).…”

“…This is consistent with previous observations that cyclin D3 knock-out mice exhibited decreased myofiber size at 21 days of regeneration and that cyclin D3 deficiency was associated with reduced proliferative capacity and impaired G 1 /S progression (31,37,38). In contrast, cyclin D3 overexpression promotes myogenic differentiation as demonstrated by increased MyoD and MyoG expression (37).…”

“…Although skeletal muscle regeneration mimics a developmental process, the actual role of lipin1 in skeletal muscle development remains to be explored. Cyclin D3 plays a cell-autonomous and non-redundant function in regulating the satellite cell pool involved in proliferation, differentiation, and self-renewal (31). Because lipin1 deficiency suppresses cyclin D3 expression, it would be important to evaluate this effect on satellite cell population and function.…”

Actions of 1,25(OH)2-vitamin D3 on the cellular cycle depend on VDR and p38 MAPK in skeletal muscle cells

“…This clearly shows that the beginning of the differentiation program induced by 1,25D in C2C12 cells requires the expression of the VDR and activation of p38. However, in cyclin D3-deficient C2.7 myoblasts, changes in myogenin expression were not found (De Luca et al 2013). This may be explained by differences in experimental design (like the use of differentiation medium) or other pathways which are not regulated by 1,25D being involved in myogenin expression.…”

Activation of TLR7 increases CCND3 expression via the downregulation of miR-15b in B cells of systemic lupus erythematosus

“…8,11,38,39 However, the study of CCND3 regulation in B cells is yet to be fully understood. In this study, we first found that elevated CCND3 was associated with SLE based on gene profiling analysis.…”