Language

English

Publication Date

9-26-2025

Journal

Circulation Research

DOI

10.1161/CIRCRESAHA.125.326550

PMID

40910184

PMCID

PMC12676482

PubMedCentral® Posted Date

12-6-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Background: Calcium (Ca2+) dysregulation is a hallmark of heart failure, impairing excitation-contraction coupling and contributing to pathological remodeling. The sarco/endoplasmic reticulum Ca2+ ATPase isoform 2a (SERCA2a) mediates Ca2+ reuptake into the sarcoplasmic reticulum (SR) during diastole, but its activity declines in failing hearts. DWORF (dwarf open reading frame), a newly identified cardiac microprotein, enhances SERCA2a activity and improves cardiomyocyte Ca2+ cycling and contractility. SR Ca2+ release also influences mitochondrial metabolism and ATP production. Here, we investigated whether DWORF overexpression improves SR Ca2+ handling, augments mitochondrial Ca2+ signaling, and protects against heart failure progression.

Methods: Transgenic and adeno-associated virus approaches were used to overexpress DWORF in the heart. Mice underwent transverse aortic constriction (TAC) to model pressure overload-induced heart failure. Cardiac function, mitochondrial metabolism, SR Ca2+ uptake, and remodeling were assessed.

Results: Mitochondria from DWORF transgenic hearts displayed increased basal respiration, maximal respiration, and spare respiratory capacity, correlating with enhanced mitochondrial Ca2+ uptake kinetics. Western blot analysis showed elevated levels of active PDH (pyruvate dehydrogenase) and mitochondrial Ca2+ uniporter expression in DWORF transgenic hearts, supporting a role for DWORF in Ca2+-driven metabolic regulation. Similarly, MyoAAV (myo-adeno-associated virus)-mediated DWORF overexpression enhanced mitochondrial respiration and increased levels of active PDH in adult mice. Following TAC, MyoAAV-DWORF-treated mice maintained higher left ventricular function and were protected from further deterioration compared with controls. This benefit was observed when DWORF gene therapy was delivered preventively at the time of pressure overload or after heart failure was already established. DWORF gene therapy also attenuated remodeling, with lower heart weight and lung weight-to-tibia length ratios. Seahorse analysis confirmed sustained mitochondrial improvements in both treatment paradigms.

Conclusions: DWORF overexpression enhances SR Ca2+ dynamics, improves mitochondrial energetics, and attenuates pathological remodeling and heart failure progression in response to pressure overload. These findings support DWORF as a promising therapeutic target for heart failure.

Keywords

Animals, Mitochondria, Heart, Mice, Transgenic, Genetic Therapy, Mice, Heart Failure, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Calcium, Myocytes, Cardiac, Male, Sarcoplasmic Reticulum, Mice, Inbred C57BL, Calcium Signaling, Dependovirus, Disease Models, Animal, Cardiomyopathy, Heart Failure, Calcium cycling/excitation-contraction coupling, basic science research

Published Open-Access

yes

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