Senescence plays a role in myotonic dystrophy type 1

Abstract

Myotonic dystrophy type 1 (DM1; MIM #160900) is an autosomal dominant disorder, clinically characterized by progressive muscular weakness and multisystem degeneration. The broad phenotypes observed in DM1 patients resemble the appearance of an accelerated aging process. However, the molecular mechanisms underlying these phenotypes remain largely unknown. Transcriptomic analysis of fibroblasts derived from DM1 patients and healthy individuals revealed a decrease in cell cycle activity, cell division, and DNA damage response in DM1, all of which related to the accumulation of cellular senescence. The data from transcriptome analyses were corroborated in human myoblasts and blood samples as well as in mouse and Drosophila models of the disease. Serial passage studies in vitro confirmed the accelerated increase in senescence and the acquisition of a senescence-associated secretory phenotype in DM1 fibroblasts, whereas DM1 Drosophila model showed reduced longevity and impaired locomotor activity. Moreover, functional studies highlighted the impact of BMI1 and downstream p16 INK4A /RB and ARF/p53/p21 CIP pathways in DM1-associated cellular phenotypes. Importantly, treatment with the senolytic compounds, Quercetin, Dasatinib, or Navitoclax, reversed the accelerated aging phenotypes in both DM1 fibroblasts in vitro and in Drosophila in vivo. Our results identified the accumulation of senescence as part of DM1 pathophysiology and therefore, demonstrated the efficacy of senolytic compounds in the pre-clinical setting.

Quercetin selectively reduces expanded repeat RNA levels in models of myotonic dystrophy

“…Quercetin and other flavonoids including fisetin have been described as senolytics, compounds that selectively induce cell death in senescent cells ( 23 ). Recent studies demonstrated that accelerated senescence, which is observed in myotonic dystrophy models, could be modulated using senolytics ( 24, 25 ). In these studies, senolytic treatment reduced key molecular markers of senescence including p16 in cellular and animal models of DM1, supporting senolytics as potential therapeutics for DM ( 24, 25 ).…”

“…Recent studies demonstrated that accelerated senescence, which is observed in myotonic dystrophy models, could be modulated using senolytics ( 24, 25 ). In these studies, senolytic treatment reduced key molecular markers of senescence including p16 in cellular and animal models of DM1, supporting senolytics as potential therapeutics for DM ( 24, 25 ). However, the effects of quercetin and/or other senolytics on key molecular hallmarks of RNA toxicity including mis-splicing were not determined ( 24, 25 ).…”

“…The mechanism of action however was not determined, and the effects of flavonoids on toxic CUG RNA pathogenesis were not tested. More recently, quercetin was also evaluated as a senolytic for treatment of DM1 ( 24, 25 ). In these studies, DM1 cells were reported to express the senescence associated secretory phenotype (SASP) and could be targeted by quercetin alone ( 25 ) or in combination with dasatinib ( 24 ).…”

“…More recently, quercetin was also evaluated as a senolytic for treatment of DM1 ( 24, 25 ). In these studies, DM1 cells were reported to express the senescence associated secretory phenotype (SASP) and could be targeted by quercetin alone ( 25 ) or in combination with dasatinib ( 24 ). Both treatments lead to the induction of cell death in senescent DM1 cells.…”

“…Both treatments lead to the induction of cell death in senescent DM1 cells. Quercetin treatment was also determined to prolong lifespan in a DM1 Drosophila model ( 25 ). While a senolytic effect was reported to be of therapeutic benefit in DM by reducing the senescent cell population and improving myogenic potential, the effects of quercetin and other senolytics on the molecular hallmarks of toxic CUG RNA including DM associated MBNL dependent mis-splicing were not reported.…”