Article

Transcriptomic Bioinformatics Analysis Reveals DJ-1-Associated Redox Imbalance and Mitochondrial Dysfunction in Muscle Disease

Hye Lin Kim^1,5, Yeon-gyeong Kim^2,5, Jaehyeon Kim³, Kang Pa Lee^4,*

Abstract

Background/Objectives: DJ-1, encoded by PARK7, is a redox-sensitive multifunctional protein involved in antioxidant defense, mitochondrial homeostasis, and cellular stress responses. Although DJ-1 has been widely investigated in neurodegenerative disease, its transcriptomic association with muscle disease and muscle atrophy remains insufficiently characterized. This study aimed to identify DJ-1-associated redox and mitochondrial gene expression patterns in muscle disease using bioinformatics-based transcriptomic analysis.

Methods: Transcriptomic profiles from normal muscle and muscle disease or muscle atrophy samples were analyzed. PARK7 expression and selected antioxidant, mitochondrial, autophagy-related, and muscle atrophy-associated genes were evaluated. Differential expression analysis, gene set enrichment analysis (GSEA), volcano plot visualization, violin plot analysis, heatmap clustering, log2 fold change-based comparison, and pathway-level interpretation were performed.

Results: Muscle disease samples showed significant alteration of antioxidant response gene expression patterns, including enrichment of redox-related genes (NES = 1.6, FDR < 0.01). PARK7 expression showed disease-associated dysregulation rather than a uniform decrease. Heatmap and differential expression analyses revealed reduced expression of antioxidant and mitochondrial homeostasis genes, including SOD2, GPX4, CAT, PRDX3, PPARGC1A, TFAM, MFN2, and OPA1. In contrast, stress-response and muscle atrophy-associated genes, including NFE2L2/NRF2, SQSTM1/p62, HMOX1, NQO1, TRIM63/MuRF1, FBXO32/Atrogin-1, and FOXO1, were increased.

Conclusions: These findings suggest that muscle disease and muscle atrophy are associated with DJ-1-related redox imbalance, impaired mitochondrial homeostasis, and compensatory activation of NFE2L2/NRF2-p62-HMOX1 stress-response pathways. DJ-1 may serve as a functional node linking oxidative stress, mitochondrial dysfunction, and muscle degeneration.

Keywords

DJ-1, PARK7, oxidative stress, muscle atrophy, mitochondrial dysfunction, transcriptomics

Introduction

Skeletal muscle is a highly metabolic tissue that depends on mitochondrial oxidative phosphorylation, redox balance, and proteostatic control to maintain contractile function. In muscle disease and muscle atrophy, oxidative stress, mitochondrial dysfunction, inflammation, and accelerated protein degradation converge to impair muscle integrity and function. Excessive reactive oxygen species (ROS) can damage proteins, lipids, and mitochondrial components, thereby promoting catabolic signaling and muscle degeneration [1–3].

DJ-1, encoded by PARK7, is a multifunctional redox-sensitive protein that participates in antioxidant defense, mitochondrial protection, protein quality control, and stress adaptation. DJ-1 has been studied primarily in the context of Parkinson disease and neurodegeneration, but its broader role in non-neuronal tissues, including skeletal muscle, is increasingly relevant because muscle degeneration is strongly associated with oxidative and mitochondrial stress [4–6].

In skeletal muscle, impaired antioxidant defense may accelerate myofiber damage and activate muscle atrophy programs. Canonical atrophy-related genes such as TRIM63/MuRF1 and FBXO32/Atrogin-1 are commonly induced under catabolic conditions, whereas mitochondrial biogenesis and maintenance genes such as PPARGC1A, TFAM, MFN2, and OPA1 are often reduced during muscle dysfunction [7–9]. Whether DJ-1-associated redox and mitochondrial gene networks are altered in muscle disease remains an important question.

This study used transcriptomic bioinformatics analysis to evaluate PARK7/DJ-1 expression and DJ-1-associated antioxidant, mitochondrial, stress-response, and muscle atrophy-related gene expression patterns in normal and diseased muscle datasets. We hypothesized that muscle disease and muscle atrophy are characterized by DJ-1-related redox dysregulation, reduced mitochondrial homeostasis, and compensatory stress-response signaling.

Materials and Methods

Transcriptomic dataset selection

Publicly available or internally curated transcriptomic datasets comparing normal muscle tissues with muscle disease or muscle atrophy samples were used for analysis. Dataset accession numbers, sample metadata, platform information, normalization method, and inclusion/exclusion criteria should be inserted before final submission.

Gene set and target gene selection

A DJ-1-associated redox and mitochondrial gene panel was constructed to include PARK7, antioxidant defense genes (SOD2, GPX4, CAT, PRDX3, NQO1, GCLC), mitochondrial homeostasis genes (PPARGC1A, TFAM, MFN2, OPA1, BNIP3), stress-response genes (NFE2L2/NRF2, HMOX1, SQSTM1/p62), and muscle atrophy-associated genes (TRIM63/MuRF1, FBXO32/Atrogin-1, FOXO1, FOXO3). The biological categories and rationale for these genes are summarized in Table 1.

Differential expression analysis

Differentially expressed genes (DEGs) between control and disease or atrophy groups were identified using normalized transcriptomic expression data. Volcano plots were generated to visualize log2 fold change and statistical significance. Log2 fold change cutoffs and adjusted P-value thresholds should be specified according to the final dataset analysis pipeline.

Gene set enrichment analysis

Gene set enrichment analysis (GSEA) was performed to determine whether antioxidant response and hallmark pathway gene sets were significantly altered between normal and disease conditions. Normalized enrichment score (NES), nominal P-value, and false discovery rate (FDR) were used to interpret pathway-level changes.

Heatmap and visualization

Z-score-based heatmaps were generated to visualize relative expression patterns of DJ-1-associated redox, mitochondrial, stress-response, and atrophy-related genes. Violin plots were used to compare PARK7 expression distribution between groups.

Statistical analysis

Quantitative comparisons between two groups were analyzed using Student’s t-test unless otherwise specified. Data are presented as mean ± standard deviation (SD). Statistical significance was defined as *P < 0.05, **P < 0.01, and ***P < 0.001. Multiple-testing correction should be reported for genome-wide or pathway-level analyses.

Results

DJ-1-associated antioxidant gene expression patterns are altered in muscle disease

Muscle disease was associated with widespread remodeling of DJ-1-associated antioxidant pathways. Gene set enrichment analysis (GSEA) demonstrated significant enrichment of the antioxidant response gene set in muscle disease samples compared with normal muscle (NES = 1.6, FDR < 0.01; Figure 1A), indicating global remodeling of redox-associated transcriptional programs.

Consistent with this observation, volcano plot analysis identified differential expression of multiple genes involved in antioxidant defense, mitochondrial function, and oxidative stress responses, including PARK7 (DJ-1), SOD2, GPX4, TFAM, NFE2L2/NRF2, and SQSTM1 (Figure 1B). Notably, antioxidant and mitochondrial regulatory genes generally exhibited reduced expression, whereas several stress-response genes were upregulated, suggesting activation of compensatory oxidative stress pathways.

Violin plot analysis further demonstrated disease-associated dysregulation of PARK7 expression rather than a uniform decrease, with an overall trend toward increased transcript abundance in muscle disease samples (Figure 1C). This finding suggests that DJ-1 expression may be induced in response to oxidative and metabolic stress as a compensatory adaptation. However, the concomitant suppression of multiple antioxidant and mitochondrial protective genes indicates that increased PARK7 transcript levels alone may be insufficient to maintain redox homeostasis during muscle disease.

Collectively, these findings demonstrate that muscle disease is characterized by coordinated remodeling of DJ-1-associated antioxidant pathways, involving both global transcriptional changes and altered expression of key redox regulatory genes. These transcriptomic alterations provide the basis for subsequent analyses of DJ-1-associated antioxidant and mitochondrial gene networks in muscle atrophy.

Coordinated dysregulation of DJ-1-associated antioxidant and mitochondrial gene networks

Heatmap analysis revealed coordinated remodeling of DJ-1-associated antioxidant, mitochondrial, and stress-response gene networks in muscle atrophy (Figure 2A). Compared with normal muscle, genes involved in antioxidant defense and mitochondrial homeostasis, including PARK7 (DJ-1), SOD2, PPARGC1A, TFAM, and BNIP3, exhibited consistently reduced expression. In contrast, muscle atrophy-associated genes (TRIM63/MuRF1, FBXO32/Atrogin-1, and FOXO1) together with the autophagy-related gene SQSTM1/p62 were markedly upregulated, indicating activation of proteolytic and cellular stress-response pathways.

A focused heatmap of the antioxidant gene signature further confirmed coordinated suppression of antioxidant and mitochondrial protective genes (Figure 2B). Expression of DJ-1 (PARK7), SOD2, GPX4, CAT, TFAM, and PPARGC1A was consistently decreased in muscle atrophy, whereas NRF2 and SQSTM1/p62 were increased, suggesting activation of compensatory oxidative stress-response signaling. Although NRF2-dependent stress-response genes were induced, this compensatory response was accompanied by persistent downregulation of multiple antioxidant and mitochondrial maintenance genes, indicating an overall disruption of redox homeostasis rather than restoration of antioxidant capacity.

Collectively, these findings demonstrate that muscle atrophy is characterized by coordinated suppression of DJ-1-associated antioxidant and mitochondrial protective programs together with activation of oxidative stress-response and proteolytic signaling pathways.

PARK7/DJ-1-associated antioxidant failure is a hallmark of muscle atrophy

To validate the transcriptomic alterations identified in the preceding analyses, an independent muscle atrophy dataset was analyzed (Figure 3). Heatmap analysis demonstrated a consistent transcriptional shift from antioxidant and mitochondrial maintenance toward oxidative stress and muscle atrophy-associated programs (Figure 3A). Compared with normal muscle, expression of genes involved in antioxidant defense and mitochondrial homeostasis, including PARK7 (DJ-1), SOD2, GPX4, Catalase, PRDX3, NQO1, PPARGC1A (PGC-1α), TFAM, MFN2, and OPA1, was broadly reduced across muscle atrophy samples.

Quantitative analysis further confirmed significant reductions in representative antioxidant and mitochondrial protective genes, including DJ-1 (PARK7), SOD2, GPX4, Catalase, PRDX3, NQO1, PGC-1α, and TFAM, compared with normal muscle (Figure 3B). In contrast, genes associated with oxidative stress adaptation and muscle proteolysis, including NFE2L2 (NRF2), HMOX1, SQSTM1/p62, TRIM63 (MuRF1), FBXO32 (Atrogin-1), and BNIP3, were consistently increased.

Log₂ fold-change analysis further highlighted this coordinated transcriptional remodeling (Figure 3C). Antioxidant and mitochondrial maintenance genes exhibited predominantly negative fold changes, whereas stress-response and muscle atrophy-associated genes displayed positive fold changes. Notably, despite increased expression of the NRF2–HMOX1–SQSTM1/p62 stress-response axis, the persistent suppression of multiple antioxidant enzymes and mitochondrial regulators indicates that activation of compensatory antioxidant signaling is insufficient to restore redox homeostasis during muscle atrophy.

Collectively, these findings demonstrate that muscle atrophy is characterized by coordinated impairment of DJ-1-associated antioxidant defense and mitochondrial maintenance, accompanied by activation of oxidative stress-response and proteolytic pathways. These observations support DJ-1-associated antioxidant failure as a characteristic molecular feature of skeletal muscle atrophy.

Hallmark pathway analysis supports global metabolic and inflammatory remodeling in muscle atrophy

To determine whether the DJ-1-associated antioxidant signature reflected broader transcriptomic alterations, an independent bulk RNA-sequencing dataset (GSE217576) was analyzed (Figure 4). Differential expression analysis identified extensive transcriptional remodeling between control and muscle atrophy samples, with numerous significantly upregulated and downregulated genes, as illustrated by the volcano plot (Figure 4A). Hierarchical clustering further demonstrated clear separation between control and muscle atrophy groups, indicating distinct global transcriptional profiles associated with muscle degeneration (Figure 4B).

To investigate the biological pathways underlying these transcriptional changes, Hallmark Gene Set Enrichment Analysis (GSEA) was performed. Pathway enrichment analysis revealed significant alterations in multiple metabolic and inflammatory pathways, including oxidative phosphorylation, fatty acid metabolism, adipogenesis, glycolysis, and TNFα signaling via NF-κB (Figure 4C). Among these, oxidative phosphorylation showed the strongest enrichment, suggesting substantial disruption of mitochondrial energy metabolism during muscle atrophy. In parallel, enrichment of fatty acid metabolism and adipogenesis pathways indicates metabolic reprogramming, whereas activation of TNFα signaling via NF-κB supports increased inflammatory signaling in atrophic muscle.

Representative enrichment plots further confirmed coordinated regulation of these hallmark pathways (Figure 4D). Oxidative phosphorylation, fatty acid metabolism, and adipogenesis exhibited marked transcriptional remodeling, whereas glycolysis and inflammatory signaling through TNFα/NF-κB were also significantly altered, reflecting widespread metabolic adaptation accompanied by chronic oxidative and inflammatory stress.

Collectively, these genome-wide transcriptomic analyses demonstrate that the DJ-1-associated antioxidant signature identified in earlier analyses is embedded within a broader molecular program characterized by impaired mitochondrial metabolism, metabolic reprogramming, and activation of inflammatory pathways during muscle atrophy. These findings further support the hypothesis that disruption of DJ-1-associated redox homeostasis contributes to global metabolic dysfunction and progressive muscle degeneration.

Proposed working model of DJ-1-associated redox imbalance in muscle atrophy

Taken together, our transcriptomic analyses suggest that muscle disease and muscle atrophy are characterized by coordinated disruption of DJ-1-associated antioxidant and mitochondrial homeostasis, accompanied by activation of oxidative stress-response and proteolytic pathways. Based on these findings, we propose a working model illustrating the potential role of DJ-1 in regulating redox balance during muscle degeneration (Figure 5). Under physiological conditions, DJ-1 contributes to the maintenance of antioxidant defense and mitochondrial homeostasis by supporting the expression of antioxidant enzymes and mitochondrial regulatory factors, thereby preserving intracellular redox balance and skeletal muscle integrity. In contrast, muscle disease or atrophy is associated with functional dysregulation of DJ-1, accompanied by reduced expression of antioxidant defense genes (e.g., SOD2, GPX4, and CAT) and mitochondrial maintenance genes (e.g., PGC-1α and TFAM). These alterations are associated with compensatory activation of the NFE2L2/NRF2–SQSTM1/p62–HMOX1 stress-response axis, induction of the muscle atrophy-associated genes TRIM63 (MuRF1) and FBXO32 (Atrogin-1), increased oxidative stress, mitochondrial dysfunction, and progressive muscle degeneration. Collectively, these findings support a model in which DJ-1-associated redox dysregulation contributes to the molecular mechanisms underlying muscle atrophy.

Discussion

This study provides a transcriptomic bioinformatics-based analysis of DJ-1-associated redox and mitochondrial gene expression patterns in muscle disease and muscle atrophy. The major findings are summarized as follows: first, antioxidant response gene expression patterns were significantly altered in muscle disease; second, PARK7/DJ-1 showed disease-associated expression dysregulation; third, antioxidant and mitochondrial homeostasis genes were reduced; and fourth, compensatory stress-response genes and muscle atrophy markers were increased.

DJ-1 is a redox-sensitive protein that can respond to oxidative stress and mitochondrial damage. In the present analysis, PARK7 expression did not follow a simple uniform decrease across disease contexts. Instead, the pattern supports a model of functional dysregulation. In this interpretation, transcriptional PARK7 changes may reflect compensatory stress adaptation or insufficient DJ-1 function in the setting of persistent oxidative stress.

The reduction of SOD2, GPX4, CAT, PRDX3, PPARGC1A, TFAM, MFN2, and OPA1 suggests impaired ROS detoxification and mitochondrial maintenance in muscle disease and atrophy. These changes are biologically consistent with muscle degeneration because skeletal muscle requires intact mitochondrial function and redox balance for energy production, contractility, and proteostasis.

The concomitant increase in NFE2L2/NRF2, HMOX1, SQSTM1/p62, TRIM63/MuRF1, and FBXO32/Atrogin-1 suggests that reduced antioxidant and mitochondrial protective capacity is accompanied by compensatory stress signaling and activation of muscle protein degradation pathways. NFE2L2/NRF2 and HMOX1 may reflect an attempt to counter oxidative injury, whereas SQSTM1/p62 may indicate altered autophagy or protein quality control. However, transcriptomic data alone cannot establish protein activity or causal direction.

This study has several limitations. First, the analysis is based on transcriptomic datasets and therefore requires validation at the protein and functional levels. Second, dataset-specific heterogeneity, including disease subtype, tissue source, age, sex, sample processing, and platform differences, should be carefully controlled. Third, mitochondrial function, ROS levels, and DJ-1 protein oxidation status were not directly measured. Future studies should validate these findings using qPCR, Western blotting, immunofluorescence, ROS assays, mitochondrial membrane potential analysis, and functional knockdown or overexpression experiments.

Conclusion

This bioinformatics study suggests that muscle disease and muscle atrophy are associated with DJ-1-related redox imbalance, antioxidant defense failure, mitochondrial homeostasis disruption, and compensatory activation of NFE2L2/NRF2-p62-HMOX1 stress-response pathways.

The overall transcriptomic pattern supports a model in which DJ-1 dysregulation is linked to reduced antioxidant and mitochondrial protective capacity, increased stress signaling, and activation of muscle atrophy-related genes. DJ-1 may therefore represent a candidate functional node and biomarker for future studies of oxidative stress-associated muscle degeneration. Experimental validation is required to determine whether DJ-1 is a causal regulator or compensatory marker in muscle disease.

Funding

This section should be completed according to the funding sources supporting the study.

Acknowledgments

The authors thank the members of UMUST R&D corporation for technical discussion and manuscript preparation support.

Conflict of Interest

The authors declare no conflict of interest. This statement should be revised if any competing interests exist.

Author Contributions

Conceptualization, S.B. and K.P.L.; methodology, S.B., H.Y.L., and J.K., Y.-G.K; formal analysis, S.B., H.Y.L., J.K., and Y.-G.K; investigation, S.B. and K.P.L.; writing-original draft preparation, S.B.; writing-review and editing, K.P.L.; supervision, K.P.L. All authors have read and agreed to the published version of the manuscript.

Data Availability Statement

The transcriptomic datasets and analysis code should be deposited or described before submission. Dataset accession numbers and repository links should be inserted here.

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