Hair follicles (HFs) in the growth stage (anagen) exhibit a great degree of cell division. On top of this, there is a high rate of protein synthesis to support keratinization of the growing hair fiber. As a result, the HF must have access to an ample supply of adequate nutrients, which are then metabolized to provide not only energy, but also molecular “building blocks” for hair growth. Here, the HF adopts a strategy also employed by other highly proliferative cells, such as activated lymphocytes and cancer cells: aerobic glycolysis. In other words, despite a high abundance of functional mitochondria and oxygen capable of respiration, the HFs secrete 90% of the glucose as lactate.
It is well established that aerobic glycolysis occurs in HFs, but the reason why it does so is less clear. At the same time, the outer root sheath (ORS) of the HF is reportedly rich in glycogen, which is important for keratinization and regulation of the hair cycle. Attempting to reconcile these two notions, the authors focused on the metabolic interplay between muscle and the liver: muscle tissue-derived lactate is transported to the liver and re-converted back to glucose through a process termed gluconeogenesis, protecting tissues from the toxic accumulation of lactate. Driven by all these facts and notions, the authors hypothesized that, within the HF, the lactate exported by the highly proliferative cells could be taken up by cells in the ORS and undergo gluconeogenesis followed by glycogen synthesis.
By measuring the local content of glycogen in different regions of cultured human HFs, the authors confirmed that it was mainly observed in the ORS. Interestingly, the glycogen content was higher in anagen HFs when compared to those in catagen, and HFs expressed several proteins and enzymes necessary for the transport and uptake of lactate and glucose as well as glycogen synthesis and catabolism. In line with this, keratinocytes from the ORS were able to synthesize glycogen when cultured in the presence of lactate, showcasing the existence of an intrafollicular, compartmentalized Cori cycle within the HF.
Finally, to understand what the physiological relevance of this glycogen synthesis might be, the authors treated HFs with an inhibitor of glycogen phosphorylase, the rate-limiting enzyme in the degradation of glycogen (glycogenolysis). Surprisingly, inhibiting glycogenolysis in cultured HFs led to a prolongation of anagen, suggesting that degradation of accumulated glycogen may actively promote the transition to catagen. From a clinical perspective, these results suggest that local manipulation of HF metabolism may be a strategy to halt hair loss and promote hair growth.
‘Human hair follicles operate an internal Cori cycle and modulate their growth via glycogen phosphorylase’
Sci Rep. 2021 Oct 21. doi: 10.1038/s41598-021-99652-8.