BACKGROUND: Males and females exhibit distinct anatomic and functional characteristics of the heart, predisposing them to specific disease states. METHODS: We identified microRNAs (miRNAs/miR) with sex-differential expression in mouse hearts. RESULTS: Four conserved miRNAs are present in a single locus on the X-chromosome and are expressed at higher levels in females than males. We show miRNA, miR-871, is responsible for decreased expression of the protein SRL (sarcalumenin) in females. SRL is involved in calcium signaling, and we show it contributes to differences in electrophysiology between males and females. miR-871 overexpression mimics the effects of the cardiac physiology of conditional cardiomyocyte-specific Srl-null mice. Inhibiting miR-871 with an antagomir in females shortened ventricular repolarization. The human orthologue of miR-871, miR-888, coevolved with the SRL 3′ untranslated region and regulates human SRL. CONCLUSIONS: These data highlight the importance of sex-differential miRNA mechanisms in mediating sex-specific functions and their potential relevance to human cardiac diseases.

BACKGROUND: Atrial fibrillation, the most common sustained arrhythmia, affects 59 million individuals worldwide. The transcription factor TBX5 (T-box 5) is essential for normal atrial rhythm. Its inactivation causes loss of atrial cardiomyocyte (aCM) enhancer accessibility, looping, transcriptional identity, and spontaneous atrial fibrillation. TBX5 interacts with CHD4 (chromodomain helicase DNA-binding protein 4), a chromatin remodeling ATPase canonically associated with the NuRD (nucleosome remodeling and deacetylase) repressor complex. METHODS: We investigated mechanisms by which TBX5 regulates chromatin organization by studying mice with aCM-selective inactivation of TBX5 or CHD4. We integrated multiple genomics approaches including concurrent single-nucleus transcriptome and open chromatin profiling and genome-wide TBX5 and CHD4 chromatin occupancy assays. RESULTS: We found that TBX5 recruits CHD4 to 33 170 genomic regions (TBX5-enhanced CHD4 sites). In addition to the canonical repressive activity of CHD4, we uncovered a CHD4 activator function predominantly at sites to which it was recruited by TBX5. TBX5-enhanced CHD4 recruitment increased local chromatin accessibility and promoted the expression of aCM identity genes. This mechanism of CHD4 recruitment by TBX5 was crucial for sinus rhythm; mice with CHD4 inactivation in aCMs had increased atrial fibrillation vulnerability. Assaying TBX5 binding in Chd4 ^AKO atria demonstrated that CHD4 also promotes TBX5 binding at >10 000 genomic loci, including 3051 TBX5-enhanced CHD4 sites. Consistent with its requirement to maintain normal atrial rhythm, CHD4 was implicated in the regulation of 42 genes linked to atrial fibrillation in humans. Nine had the hallmarks of TBX5-dependent, CHD4-mediated transcriptional activation. CONCLUSIONS: Our findings reveal that normal atrial rhythm requires CHD4, which activates and represses atrial genes in a context-dependent manner to maintain aCM gene expression, aCM identity, and atrial rhythm homeostasis.

Background/Objectives: Chemotherapy-induced neuropathic pain (CINP) represents a critical challenge in oncology, emerging as a common and debilitating side effect of widely used chemotherapeutic agents, such as paclitaxel (PTX). Current therapeutic interventions and preventive strategies for CINP are largely insufficient, as they fail to address the underlying peripheral nerve damage, highlighting an urgent need for the development of new drugs. This study aimed to investigate the dual-function effects on normal cell protection and tumor suppression of BMX-001, a redox-active manganese metalloporphyrin that has demonstrated antioxidant and anti-inflammatory properties, which offers potential in protecting central nervous system tissues and treating CINP. Methods: This study assessed BMX-001’s different roles in protecting normal cells while acting as a pro-oxidant and pro-inflammatory molecule in cancer cells in vitro. We also evaluated its neuroprotective effect in preclinical PTX-induced CINP models in vivo. Results: Our results showed significant reductions in mechanical and cold allodynia, decreased pro-inflammatory cytokine levels, and restored antioxidant capacity in peripheral nerves and dorsal root ganglia (DRGs) following BMX-001 treatment. Conclusions: Overall, our study highlights the therapeutic potential of BMX-001 to mitigate CINP and enhance anticancer efficiency. Its dual-selective mechanism supports the future clinical investigation of BMX-001 as a novel adjunct to chemotherapeutic regimens.