Abstract Body: Introduction: The heart adapts to changes in metabolism or load by adapting cardiomyocyte size. In this context cardiac atrophy can be the consequence of unloading, nutritional deficit, or inflammation and can lead to heart failure and death if not reversed. We previously demonstrated that p21-activated kinase (Pak1) signaling is cardioprotective and regulates cardiomyocyte growth. Here we tested the hypothesis that Pak1 is a prerequisite in cardiomyocytes recovery from atrophy.
Methods: Cardiac atrophy was induced in mice (WT, Pak1^-/-) through fasting (72h) or inflammation (dextran sulfate sodium: 3.5%, 7 days (d)). Recovery from atrophy was quantified after 6d, or 21d, respectively. Heart weight (HW) was normalized to tibia length (TL). Cardiomyocyte size was characterized by area or capacitance.
Results: During peak inflammation mice exhibited a 14.6% (±6.78%, n=16) and fasted mice a 16.9% (±1.73%, n=14) loss of body weight. Animals regained their weight within 21d or 6d, respectively. WT and Pak1^-/- hearts exhibited comparable decreases in HW (WT_DSS: 20.84±3.33%, Pak1_DSS: 17.74±4.82%, p=0.332) but while WT HW fully recovered (WT_DSS 0.26±6.95%, p=0.938), Pak1^-/- HW remained significantly reduced (Pak1_DSS: 15.49±4.40%, p =0.010). Similar changes were found in fasted mice: fasting induced a comparable decrease in WT and Pak1^-/- HWs (WT_Fast: 22.96±5.98%, Pak_Fast: 20.32±5.45%, p=0.544) however, Pak1^-/- HW failed to recover following refeeding (WT_Fast: 6.10±2.77%, p=0.474; Pak_Fast: 30.97±4.57%, p=0.014). The same effect was observed when WT animals were treated with the Pak1 inhibitor IPA3 (5mg/kg) during the recovery from inflammation or fasting. Both WT and Pak1^-/- groups saw declines in atrial myocyte area compared to controls (WT: 39.40±14.57%, p<0.001; Pak: 27.32±18.45%, p=0.006) and increased cellular autophagy demonstrating that loss in HW was the consequence of cellular catabolism.
Conclusion: The data show for the first time that Pak1 is a prerequisite for cardiac recovery from atrophy, and that attenuated Pak1 signaling reduces cardiac plasticity thereby increasing the risk for pathophysiological remodeling.