This study delves into the mechanisms by which a short period of fasting can accelerate wound healing. Fasting triggers many of the same cellular stress responses, such as upregulated autophagy, as occur during the practice of calorie restriction. It isn't exactly the same, however, so it is always worth asking whether any specific biochemistry observed in either case does in fact occur in both situations. In particular, the period of refeeding following fasting appears to have beneficial effects that are distinct from those that occur while food is restricted.
Multiple forms of therapeutic fasting have been reported regarding their efficacy to improve health (decreasing body fat and blood pressure, promoting stem cell function and regeneration, reversing immunosuppression, suppressing inflammation, etc.), delay aging and extend life span. Recently, it was shown that fasting for 48 h during a 4-day observation period after stroke was able to augment angiogenesis in ischemic brain and alleviate cerebral ischemic injury in mice; periodic fasting (a 48-hour period of fasting per week for one month) resulted in reduced cortical atrophy and long-term neurobehavioral improvement. Nonetheless, the regulatory molecular mechanism through which fasting affects angiogenesis remains unclear.
Here, we generated full-thickness excisional or burn skin wounds in streptozotocin-induced diabetic mice and normal mice, respectively, and determined whether fasting prior to or after wound injury for a certain period of time can promote angiogenesis and speed up the process of wound healing. In vitro, we evaluated the effects of fasting and refeeding on the proliferation, migration and angiogenic tube formation of endothelial cells. To further explore the molecular mechanism, transcriptome sequencing of fasting and non-fasting endothelial cells was conducted to screen the differentially expressed angiogenesis-related genes and the role of the candidate genes in the fasting-induced promotion of angiogenesis was demonstrated.
Two times of 24-h fasting in a week after but especially before wound injury efficiently induced faster wound closure, better epidermal and dermal regeneration, less scar formation and higher level of angiogenesis in mice with diabetic or burn wounds. Transcriptome sequencing revealed that fasting itself, but not the following refeeding, induced a prominent upregulation of a variety of pro-angiogenic genes, including SMOC1 and SCG2. Immunofluorescent staining confirmed the increase of SMOC1 and SCG2 expression in both diabetic and burn wounds after fasting treatment. When the expression of SMOC1 or SCG2 was down-regulated, the fasting/refeeding-induced pro-angiogenic effects were markedly attenuated.