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Analyzing Oxygen Consumption Rate in Primary Cultured Mouse Neonatal Cardiomyocytes Using an Extracellular Flux Analyzer

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Short SCN5A Transcript Yields a NaV1.5 Fragment Influencing Cardiac Metabolism.

Nathan H Witmer^1,2, Jasmyn M Hoeger^1,3, Jared M McLendon^1,4

¹Department of Internal Medicine, Fraternal Order of Eagles Diabetes Research Center, Abboud Cardiovascular Research Center, Carver College of Medicine (N.H.W., J.M.H., J.M.M., C.S.S., J.-Y.Y., B.L., R.L.B.), University of Iowa.

Circulation Research

|March 11, 2026

Summary

This summary is machine-generated.

A newly discovered alternative polyadenylation signal in SCN5A generates a short transcript. This transcript encodes a mitochondrial protein (NaV1.5-NT) that enhances cardiomyocyte metabolism and may impact heart failure.

Keywords:

action potentials cardiomyopathy, dilated defibrillators, implantable mitochondria sodium channels

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Viral Transgene Expression in Rodent Hearts and the Assessment of Cardiac Arrhythmia Risk

Viral Transgene Expression in Rodent Hearts and the Assessment of Cardiac Arrhythmia Risk

Published on: July 27, 2022

Area of Science:

Cardiovascular Biology
Molecular Cardiology
Mitochondrial Metabolism

Background:

SCN5A encodes the cardiac NaV1.5 channel, crucial for action potentials and cardiomyocyte metabolism.
SCN5A variants are linked to heart failure and arrhythmias.
Mechanisms regulating SCN5A expression and its metabolic role are not fully understood.

Purpose of the Study:

To identify novel regulatory features of SCN5A.
To investigate the functional role of a conserved alternative polyadenylation (APA) signal in SCN5A.
To explore the impact of a novel SCN5A-derived protein on cardiomyocyte metabolism.

Main Methods:

Bioinformatic analysis to identify APA signals in SCN5A.
Generation of knock-in mice with a human APA signal.
Characterization of the truncated SCN5A protein isoform (NaV1.5-NT) using Western blotting, cell fractionation, and microscopy.
Assessment of mitochondrial function and metabolites in cardiomyocytes and mouse hearts.

Main Results:

A conserved APA signal downstream of SCN5A exon 2 generates a short transcript (SCN5A-short) encoding NaV1.5-NT.
NaV1.5-NT localizes to the mitochondrial matrix and enhances mitochondrial respiration, ATP production, and Complex I activity.
NaV1.5-NT expression alters cardiac metabolome, suggesting increased fatty acid oxidation.
Reduced SCN5A-short expression observed in failing human hearts.

Conclusions:

Alternative polyadenylation of SCN5A produces a mitochondrial-targeted peptide (NaV1.5-NT) that supports cardiomyocyte metabolism.
This pathway reveals novel SCN5A-mitochondrial crosstalk with implications for heart failure and arrhythmias.
Further research is needed to elucidate the precise molecular mechanisms of NaV1.5-NT function.