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<p>Prolonged bed rest or microgravity exposure, as experienced during spaceflight, profoundly impacts cardiac health. Yet, the molecular mechanisms driving these detrimental changes remain largely elusive. Hindlimb unloading (HLU), a model of simulated microgravity, induces endoplasmic-reticulum (ER) stress, and its role in maladaptive cardiac remodeling remains unknown. To investigate the impact of HLU, its underlying molecular mechanisms and the therapeutic potential of ER stress suppression, C57BL6 mice were assigned to grounded control (GC) or HLU group. HLU mice received daily vehicle or 4-phenylbutyrate (4-PBA), an ER stress inhibitor, for 21&#xa0;days. Additionally, HL-1 cardiomyocytes were treated with the ER stress inducer thapsigargin, with or without 4-PBA, to explore the cross-communication between ER stress and mitochondrial and metabolic dysfunction <i>in vitro</i>. Cardiac transcriptomic analysis revealed significant gene dysregulation in HLU compared to GC hearts. In HLU hearts, downregulated genes were mainly enriched for mitochondrial function and metabolic pathways, while upregulated genes were linked to extracellular matrix (ECM) pathways. Conversely, HLU mice treated with 4-PBA showed upregulation of mitochondrial function-related genes and downregulation of ECM-related genes. The oxidative phosphorylation (OXPHOS), which was downregulated in HLU hearts, became one of the most upregulated pathways following 4-PBA treatment. Consistent with the <i>in vivo</i> findings, thapsigargin-induced ER stress significantly compromised mitochondrial function, whereas co-treatment with 4PBA significantly preserved mitochondrial function. Together, our findings strongly suggest that prolonged bed rest or microgravity exposure triggers ER stress-induced mitochondrial and metabolic dysfunction in the heart, and pharmacological suppression of ER stress limits these detrimental cellular effects.</p> Graphical abstract <p>Schematic representation shows HLU-induced ER stress and mitochondrial dysfunction, and its reversal by 4PBA in heart. The top panel illustrates that hindlimb unloading (HLU-Vehicle) leads to endoplasmic reticulum (ER) stress (indicated by red “stress” bursts within the ER), which subsequently compromises mitochondrial function, resulting in decreased oxidative phosphorylation (OXPHOS) and reduced ATP production. This contributes to cardiac metabolic perturbation. The bottom panel demonstrates that treatment with 4-phenylbutyrate (4-PBA), an ER stress inhibitor, alleviates ER stress (fewer “stress” bursts). This suppression of ER stress, in turn, preserves mitochondrial integrity and enhances OXPHOS, leading to improved ATP production and thus mitigating HLU-induced cardiac dysfunction.</p> <p></p>

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ER stress inhibitor 4PBA attenuates hindlimb unloading-induced cardiac mitochondrial and metabolic dysfunction

  • 期刊论文

  • 发表日期：

    2025年12月16日

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  • Firdos Ahmad,
  • Anupriya Sinha,
  • Asima Karim,
  • Megna Srinivas,
  • Josemin Jose,
  • Dhanendra Tomar,
  • Rizwan Qaisar

摘要

Prolonged bed rest or microgravity exposure, as experienced during spaceflight, profoundly impacts cardiac health. Yet, the molecular mechanisms driving these detrimental changes remain largely elusive. Hindlimb unloading (HLU), a model of simulated microgravity, induces endoplasmic-reticulum (ER) stress, and its role in maladaptive cardiac remodeling remains unknown. To investigate the impact of HLU, its underlying molecular mechanisms and the therapeutic potential of ER stress suppression, C57BL6 mice were assigned to grounded control (GC) or HLU group. HLU mice received daily vehicle or 4-phenylbutyrate (4-PBA), an ER stress inhibitor, for 21 days. Additionally, HL-1 cardiomyocytes were treated with the ER stress inducer thapsigargin, with or without 4-PBA, to explore the cross-communication between ER stress and mitochondrial and metabolic dysfunction in vitro. Cardiac transcriptomic analysis revealed significant gene dysregulation in HLU compared to GC hearts. In HLU hearts, downregulated genes were mainly enriched for mitochondrial function and metabolic pathways, while upregulated genes were linked to extracellular matrix (ECM) pathways. Conversely, HLU mice treated with 4-PBA showed upregulation of mitochondrial function-related genes and downregulation of ECM-related genes. The oxidative phosphorylation (OXPHOS), which was downregulated in HLU hearts, became one of the most upregulated pathways following 4-PBA treatment. Consistent with the in vivo findings, thapsigargin-induced ER stress significantly compromised mitochondrial function, whereas co-treatment with 4PBA significantly preserved mitochondrial function. Together, our findings strongly suggest that prolonged bed rest or microgravity exposure triggers ER stress-induced mitochondrial and metabolic dysfunction in the heart, and pharmacological suppression of ER stress limits these detrimental cellular effects.

Graphical abstract

Schematic representation shows HLU-induced ER stress and mitochondrial dysfunction, and its reversal by 4PBA in heart. The top panel illustrates that hindlimb unloading (HLU-Vehicle) leads to endoplasmic reticulum (ER) stress (indicated by red “stress” bursts within the ER), which subsequently compromises mitochondrial function, resulting in decreased oxidative phosphorylation (OXPHOS) and reduced ATP production. This contributes to cardiac metabolic perturbation. The bottom panel demonstrates that treatment with 4-phenylbutyrate (4-PBA), an ER stress inhibitor, alleviates ER stress (fewer “stress” bursts). This suppression of ER stress, in turn, preserves mitochondrial integrity and enhances OXPHOS, leading to improved ATP production and thus mitigating HLU-induced cardiac dysfunction.