Pancreatic Cancer Disrupts Circadian Patterns of Gene Expression in Cardiorespiratory Muscles

Cancer cachexia, a debilitating syndrome characterized by muscle wasting, significantly impacts survival in gastrointestinal cancers like pancreatic cancer. Emerging evidence suggests a link between cancer cachexia and disrupted circadian rhythms in peripheral tissues, including locomotor muscles. However, circadian dysregulation in cardiorespiratory muscles-whose functional decline are suspected to contribute to increased morbidity and mortality in patients experiencing cachexia-remains largely unexplored.

Herein, we investigated circadian gene expression patterns in cardiorespiratory muscles during cachexia using the orthotopic KPC pancreatic cancer model. To do this, circadian transcriptomes were generated from diaphragm and heart tissues collected from Sham and KPC mice every 4 h over 24 h, beginning on Day 12 postinoculation, which, based on our prior work, reflects the onset of cachexia in this model. Rhythmically expressed genes (REGs) (P_c < 0.01) were identified using the LR_rhythmicity R package, which evaluates the goodness-of-fit (R²) to a 24-h 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.

We found that ~60% of rhythmic genes lost their circadian rhythmicity in both tissues, with distinct shifts in gene networks. Diaphragm disruptions centred 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 signalling, cellular responses to insulin and neurogenesis, with a similar, but more limited upregulation of inflammatory networks.

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.