Abstract
The Cdkn2a locus is one of the most studied tumor suppressor loci in the context of several cancer types. However, in the last years, its expression has also been linked to terminal differentiation and the activation of the senescence program in different cellular subtypes. Knock-out (KO) of the entire locus enhances the capability of stem cells to proliferate in some tissues and respond to severe physiological and non-physiological damages in different organs, including the heart. Emery–Dreifuss muscular dystrophy (EDMD) is characterized by severe contractures and muscle loss at the level of skeletal muscles of the elbows, ankles and neck, and by dilated cardiomyopathy. We have recently demonstrated, using the LMNA Δ8–11 murine model of Emery–Dreifuss muscular dystrophy (EDMD), that dystrophic muscle stem cells prematurely express non-lineage-specific genes early on during postnatal growth, leading to rapid exhaustion of the muscle stem cell pool. Knock-out of the Cdkn2a locus in EDMD dystrophic mice partially restores muscle stem cell properties. In the present study, we describe the cardiac phenotype of the LMNA Δ8–11 mouse model and functionally characterize the effects of KO of the Cdkn2a locus on heart functions and life expectancy.
Highlights
The protein p16INK4a is part of the INK4 family of proteins (INhibitor of CyclinDependent Kinase 4) together with p15INK4b, p18INK4c and p19INK4d [1]
We recently demonstrated that the absence of Lamin A in LMNA ∆8–11 −/− mice during postnatal growth causes aberrant transcriptional programs at the level of MuSCs, leading to defective identity [24,26]
LMNA ∆8–11+/+ Cdkn2a −/− mice did not exhibit an increase in cell proliferation, suggesting that in a non-dystrophic condition, the lack of Cdkn2a function does not necessarily activate cell proliferation. These results reveal that Cdkn2a plays an essential role in the regulation of cardiomyocyte fitness in the heart, and its ablation in LMNA ∆8–11 −/− dystrophic mice is enough to restore the physiological number of cardiomyocytes
Summary
The protein p16INK4a is part of the INK4 family of proteins (INhibitor of CyclinDependent Kinase 4) together with p15INK4b , p18INK4c and p19INK4d [1]. This group of regulators plays a crucial role in cell cycle inhibition and tumor suppression [2,3]. P16INK4a is transcribed from the Cdkn2a locus, alternatively called INK4/ARF (ARF, Alternative Reading Frame) on chromosome 9p21.3 [1,4,5] (Figure 1). P15INK4b , transcribed from the flanking CDKN2B locus, shares 85% identity in its amino acid sequences with p16INK4a [2]. E1α is spliced to E2 and E3 to produce p16INK4a , while E1β, upon splicing to E2 and E3, imposes a frameshift that generates p19ARF (p14ARF in human), a protein with different amino acid sequence. p15INK4b , transcribed from the flanking CDKN2B locus, shares 85% identity in its amino acid sequences with p16INK4a [2]
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