Human hair follicles operate an internal Cori cycle and modulate their growth via glycogen phosphorylase

Hair follicles (HFs) are unique, multi-compartment, mini-organs that cycle through phases of active hair growth and pigmentation (anagen), apoptosis-driven regression (catagen) and relative quiescence (telogen). Anagen HFs have high demands for energy and biosynthesis precursors mainly fulfilled by aerobic glycolysis. Histochemistry reports the outer root sheath (ORS) contains high levels of glycogen. To investigate a functional role for glycogen in the HF we quantified glycogen by Periodic-Acid Schiff (PAS) histomorphometry and colorimetric quantitative assay showing ORS of anagen VI HFs contained high levels of glycogen that decreased in catagen. qPCR and immunofluorescence microscopy showed the ORS expressed all enzymes for glycogen synthesis and metabolism. Using human ORS keratinocytes (ORS-KC) and ex vivo human HF organ culture we showed active glycogen metabolism by nutrient starvation and use of a specific glycogen phosphorylase (PYGL) inhibitor. Glycogen in ORS-KC was significantly increased by incubation with lactate demonstrating a functional Cori cycle. Inhibition of PYGL significantly stimulated the ex vivo growth of HFs and delayed onset of catagen. This study defines translationally relevant and therapeutically targetable new features of HF metabolism showing that human scalp HFs operate an internal Cori cycle, synthesize glycogen in the presence of lactate and modulate their growth via PYGL activity.

Murburn precepts for redox dynamics in glycolysis, Cori cycle and Warburg effect: Is lactate dehydrogenase a murzyme?

Physiological redox conversion of alpha-hydroxy/keto acids is believed to be reversibly carried out by (de)hydrogenases, employing nicotinamide cofactors. With lactate dehydrogenase (LDH) as example, we point out that while the utilization of NADH for the reduction of pyruvate to lactate (the post-glycolytic reaction) can be mediated via the classical Michaelis-Menten mechanism, the oxidation of lactate to pyruvate (with or without the uphill reduction of NADH) necessitates alternative physiological approaches. This reaction could be more efficiently coupled/catalyzed with/by murzyme activities, which employ diffusible reactive (oxygen) species (DRS/DROS/ROS). Such a scheme would enable the cellular system to tide over the unfavorable energy barriers of the forward reaction (~450 kJ/mol; earlier considered to be ~25 kJ/mole!), and give kinetically viable conversions. Further, the new mechanism does not necessitate any ‘smart decision-making’ by the pertinent redox isozyme(s). For LDH, the new theory explains its multimeric nature, non-variant structure of the isozymes’ active sites and accounts for why lactate is transported to the liver for further utilization within the physiological purview of Cori cycle. The theoretical insights, in silico evidence and analyses of literature herein also enrich our understanding of ‘lactic acidosis’ (in clinical context), Warburg effect and approach for cancer therapy.

Involvement of Lactate and Pyruvate in the Anti-Inflammatory Effects Exerted by Voluntary Activation of the Sympathetic Nervous System

We recently demonstrated that the sympathetic nervous system can be voluntarily activated following a training program consisting of cold exposure, breathing exercises, and meditation. This resulted in profound attenuation of the systemic inflammatory response elicited by lipopolysaccharide (LPS) administration. Herein, we assessed whether this training program affects the plasma metabolome and if these changes are linked to the immunomodulatory effects observed. A total of 224 metabolites were identified in plasma obtained from 24 healthy male volunteers at six timepoints, of which 98 were significantly altered following LPS administration. Effects of the training program were most prominent shortly after initiation of the acquired breathing exercises but prior to LPS administration, and point towards increased activation of the Cori cycle. Elevated concentrations of lactate and pyruvate in trained individuals correlated with enhanced levels of anti-inflammatory interleukin (IL)-10. In vitro validation experiments revealed that co-incubation with lactate and pyruvate enhances IL-10 production and attenuates the release of pro-inflammatory IL-1β and IL-6 by LPS-stimulated leukocytes. Our results demonstrate that practicing the breathing exercises acquired during the training program results in increased activity of the Cori cycle. Furthermore, this work uncovers an important role of lactate and pyruvate in the anti-inflammatory phenotype observed in trained subjects.