Light-Dependent Regulation of Autophagy Genes in the Heart

Cardiovascular disease remains the leading cause of mortality worldwide. Understanding how cellular quality-control pathways maintain cardiac function is essential for health, and their dysregulation contributes to cardiovascular disease. Autophagy is a key quality-control mechanism that preserves cellular homeostasis by degrading damaged organelles and proteins. Many cardiac processes such as autophagy, are regulated by the heart’s intrinsic circadian clock, which aligns endogenous rhythms with environmental light (L) and dark (D) cues. We hypothesize that light exposure drives strong changes in cardiac gene expression under normal 24-hour (h) L:D conditions, but not under constant darkness (circadian conditions, D:D), indicating direct light regulation. To test this, C57BL/6 mice were entrained to a 12:12 L:D cycle for two weeks, then randomized to 12:12 LD or 12:12 D:D for 24 h. Time was recorded as Zeitgeber Time (ZT) in L:D (ZT0 = lights-on) and Circadian Time (CT) in D:D. Mice were sacrificed by CO 2 overdose and cervical dislocation every 4 h beginning at ZT/CT 23 for 24 hours (n=4/timepoint/group). Left ventricles were collected, RNA isolated (Trizol), and gene expression quantified using Affymetrix mouse Gene 2.0 ST microarrays. GeneSpring analyses identified transcripts with >1.5-fold change (FC) from ZT23-ZT03 in L:D but < 1.5 FC in D:D. Of 33,793 transcripts analyzed, 52 met the light-responsive criteria, 10 of which are associated with autophagy. Four candidates were prioritized based on Relative Fluorescence Units (RFU). Nuclear paraspeckle assembly transcript 1 (Neat1), a stress-responsive long non-coding RNA influencing autophagy exhibited greater induction in L:D (ZT23, 205 ± 14 RFU vs. ZT3, 325 ± 32 RFU; 1.58 FC) compared to D:D (CT23, 250 ± 83 RFU vs. CT3, 290 ± 17 RFU; 1.16 FC). Nuclear receptor 4A1 (Nr4a1), involved in cardiomyocyte apoptosis during ischemia reperfusion injury (heart attack) increased in response to light (L:D, ZT23, 50 ± 5 RFU vs. ZT3, 106 ± 31 RFU; 2.10 FC) and (D:D, CT23, 49 ± 9 RFU vs. CT3, 53 ± 7 RFU; 1.09 FC). Thioredoxin interacting protein (Txnip), which modulates oxidative stress and downstream cell death pathways had a similar pattern of light responsiveness in L:D (ZT23, 618 ± 57 RFU vs, ZT3, 1527 ± 213 RFU; 2.47 FC) but not in D:D (CT23, 668 ± 105 RFU vs CT3, 726 ± 94 RFU; 1.09 FC). F-box protein 32 (Fbxo32), a ubiquitin ligase regulating autophagy, exhibited an especially strong light-dependent response (L:D, ZT23, 205 ± 11 RFU vs. ZT3, 329 ± 17 RFU; 1.60 FC) compared to (D:D, CT23, 263 ± 46 RFU vs. CT3, 257 ± 13 RFU; -1.02 FC). These findings suggest that environmental light cues regulate autophagy-related gene expression in the heart to support daily cellular growth, renewal, and repair. Disrupted light exposure may impair autophagy, leading to mitochondrial dysfunction, oxidative stress, cell death, and increased vulnerability to cardiovascular disease. Further studies will validate these transcriptional changes and determine functional consequences under circadian disruption. Funding for this lab comes from the Canadian Institutes of Health Research (CIHR) and the Heart and Stroke Foundation through Tami Martino. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.