Pancreatic cancer disrupts circadian patterns of gene expression in cardiorespiratory muscles [diaphragm circadian RNA-seq]

To do this, circadian transcriptomes were generated from diaphragm and heart tissues collected from Sham and KPC mice every four hours over 24 hours, beginning on day 12 post-inoculation, which, based on our prior work, reflects the onset of cachexia in this model. Rhythmically expressed genes (REGs) (Pc<0.01) were identified using the LR_rhythmicity R package, which evaluates the goodness-of-fit (R²) to a 24-hour sinusoidal model of transcript oscillations.

Differences in circadian patterns, including changes in amplitude, phase, and basal expression, were assessed using the LR_diff R package with P<0.05. Results. We found that ~60% of rhythmic genes lost their circadian rhythmicity in both tissues, with distinct shifts in gene networks.

Diaphragm disruptions centered on repression in basal expression and/or amplitude of core clock components and rest-phase-dependent disruptions to gene networks governing lipid and oxidative programs of metabolism and proteostasis, which were linked to an upregulation and gain of rhythmicity in inflammatory networks that peaked during the rest phase. Circadian disruptions in the heart involved loss of rhythmicity in gene networks governing cardiac function, including beta-adrenergic and cAMP signaling, cellular responses to insulin and neurogenesis, with a similar, but more limited upregulation of inflammatory networks.

Conclusions. These findings demonstrate that pancreatic cancer cachexia is associated with widespread circadian dysregulation in cardiorespiratory muscles, potentially contributing to both muscle wasting and functional decline.