Bhuyar, A. | bioRxiv Science

bioRxiv2026

PARP6-dependent vimentin ADP-ribosylation prevents myofibroblast activation in cardiac fibrosis

Cardiac fibrosis is a central driver of adverse remodeling during heart failure, yet the post-translational regulation of myofibroblast activation remains poorly defined. Here, we identified PARP6 as a mono-ADP-ribosyltransferase that repressed myofibroblast activation through the ADP-ribosylation of vimentin. PARP6 expression was reduced in failing human hearts and Parp6 haploinsufficiency in mice was sufficient to induce cardiac fibrosis. At the cellular level, PARP6 ADP-ribosylated vimentin thereby limiting actin stress fiber formation. Mechanistically, PARP6 inhibition enhanced RhoA activation and vimentin-RhoA complex formation, thus activating the RhoA-ROCK-LIMK-cofilin pathway. Consistently, Parp6 haploinsufficiency was associated with increased cofilin phosphorylation in mice hearts. In primary cardiac fibroblasts, PARP6 inhibition promoted RhoA-dependent actin stress fiber accumulation and induced myofibrotic protein expression. Together, these findings define a PARP6-vimentin(ADP-ribosylation)-RhoA axis that restrained contractility-driven fibroblast activation, indicating a cardioprotective role of PARP6 with potential therapeutic relevance for fibrotic heart disease.

molecular biology↗

bioRxiv2025

SIRT2 attenuates stress-induced skeletal muscle atrophy by inhibiting glucocorticoid receptor signaling

Skeletal muscle atrophy occurs in several diseases and is associated with chronic stress. Studies indicate that glucocorticoid receptor signalling is the major signalling pathway that mediates stress-induced muscle degeneration. Although the glucocorticoid signalling pathway is relatively well characterized, there is a need to identify modulators of this pathway that may be useful for drug targeting to ameliorate muscle atrophy. SIRT2 is a mammalian Sirtuin isoform known to mediate the longevity benefits of calorie restriction and exercise. Currently, the role of SIRT2 in regulating stress-induced skeletal muscle atrophy is unclear. Our study found that SIRT2 is a critical regulator of muscle homeostasis and is required to protect against stress-induced muscle atrophy. Interestingly, SIRT2 levels are reduced during glucocorticoid-induced muscle atrophy in mice. SIRT2 depletion exacerbates glucocorticoid-induced reduction in myotube diameter and atrophy gene expression. In contrast, SIRT2 overexpression ameliorates myotube atrophy in primary myotubes. Our findings indicate that SIRT2 knockout mice are susceptible to glucocorticoid-induced muscle atrophy, while muscle-specific SIRT2-transgenic mice exhibit improved muscle function and are protected from glucocorticoid-induced atrophy. Mechanistically, SIRT2 binds to the glucocorticoid receptor to negatively regulate its activity, possibly via deacetylation of critical residues in its DNA-binding domain. Our findings suggest that SIRT2 activation may protect against glucocorticoid-induced skeletal muscle atrophy and serve as a potential therapeutic target for treating muscle atrophy.

pathology↗