Targeting PERK-driven proteostasis signalling reveals spermidine-dependent stress resilience in the ageing heart
N Kanduri, A Miljanovic, M Levin, O Gidlof, J G Smith, M Bauza-ThorbruggeAbstract
Background
Cardiac ageing and pathological stress increase vulnerability to proteostasis imbalance and endoplasmic reticulum (ER) stress. PERK is a key ER stress sensor that coordinates translational control and adaptive remodelling through the PERK–eIF2α–ATF4 axis and has been implicated in cardiac stress contexts such as ischaemia–reperfusion and pressure overload. We investigated whether spermidine availability regulates PERK pathway activity in cardiomyocytes and the ageing heart. Spermidine declines with ageing and has been linked to improved autophagy, and cardiometabolic health.
Purpose
To determine how spermidine supplementation regulates PERK–eIF2α–ATF4 signalling and downstream proteostasis pathways in human iPSC-derived cardiomyocytes and aged female mouse hearts.
Methods
Human induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) underwent genetic (ornithine decarboxylase 1, ODC1 silencing) and pharmacological (α-difluoromethylornithine, DFMO) depletion of endogenous spermidine synthesis, followed by spermidine treatment. PERK pathway activation and downstream proteostasis-associated signalling were assessed. In parallel, 19-month-old female C57BL/6J mice received spermidine supplementation (3 mM) for 8 weeks. Myocardial tissue was analysed for PERK-associated signalling.
Results
Polyamine depletion in human iPSC-CMs altered PERK pathway activity and downstream ATF4-associated stress responses. Spermidine rescue reversed these perturbations across both depletion paradigms and was accompanied by coordinated changes in proteostasis-related readouts. In aged mouse hearts, spermidine supplementation modulated PERK-associated ER stress markers. Together, these data identify spermidine as a regulator of PERK–ATF4 signalling in human cardiomyocytes and the aged heart.
Conclusions
These data identify PERK-driven proteostasis signalling as a mechanistic hub through which spermidine tunes stress-adaptive programs in cardiomyocytes and the ageing heart. This framework supports further mechanistic and translational work to define how polyamine-dependent ER stress modulation influences cardiac resilience and pathways relevant to heart failure.