ArticleCardiovascular research2026
PKP2 orchestrates OXPHOS expression in cardiomyocytes via a PGC1α-dependent mechanism.
Article in Cardiovascular research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
0 citing papers in PubMed.
No citing paper in PubMed yet.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
14 authors.
Funding
Abstract
aimsArrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease in which most patients carry (likely) pathogenic variants in desmosomal genes, most commonly in plakophilin-2 (PKP2). While the genetic causes are well described, the molecular mechanisms driving disease progression-particularly in response to exercise-remain poorly understood. METHODS AND
resultsTo investigate disease-driving pathways in ACM, we used PKP2 mutant human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and myocardial tissue from ACM patients. Transcriptomic profiling revealed consistent downregulation of oxidative phosphorylation (OXPHOS) genes in PKP2 mutant hiPSC-CMs, which was confirmed in explanted ACM hearts carrying PKP2 variants. Reduced expression of OXPHOS-related genes was associated with lower PPARGC1A expression and decreased mitochondrial spare capacity in PKP2 mutant hiPSC-CMs. The reduction in PPARGC1A expression appeared to result, at least in part, from decreased AMPKα protein levels, a known activator of PPARGC1A previously shown to localize at the intercalated disc, as PKP2 mutant cells failed to increase PPARGC1A expression following treatment with AICAR, an AMPK activator. To directly assess whether increasing PPARGC1A expression could compensate for this defect, we overexpressed PPARGC1A, which partially restored OXPHOS gene expression and improved contractility in PKP2 mutant cells.
conclusionOur study identifies a novel transcriptional mechanism linking PKP2 loss to reduced mitochondrial function via decreased PGC1α signaling, partially through reduced AMPKα levels. Disruption of this axis reduces OXPHOS gene expression and mitochondrial function in PKP2 mutant hiPSC-CMs, potentially impairing the heart's ability to meet increased energy demands during stress, and offering a mechanistic explanation for the detrimental effects of exercise in ACM. Furthermore, these findings highlight PGC1α induction as a potential therapeutic strategy to restore OXPHOS gene expression and mitochondrial adaptability in ACM.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.