Objective In mouse, PGC1-α overexpression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. One prior study has shown that FNDC5 induces browning of subcutaneous fat in mice and mediates beneficial effects of exercise on metabolism, but a more recent study using gene expression arrays failed to detect a robust increase in FNDC5 mRNA in human muscles from exercising subjects. No prior study has reported on the physiological regulation and role of circulating irisin and FNDC5 in humans. Materials/Methods A. FNDC5 gene expression studies: We first examined tissue distribution of FNDC5 in humans. B. Cross-sectional studies: Predictors of FNDC5 mRNA expression levels were examined in muscle tissues from 18 healthy subjects with a wide range of BMI. Assays were optimized to measure circulating FNDC5 and irisin levels, and their associations with anthropometric and metabolic parameters were analyzed in two cross-sectional studies that examined 117 middle-aged healthy women and 14 obese subjects, respectively. C. Interventional studies: The effect of weight loss on FNDC5 mRNA and/or circulating irisin levels was examined in 14 obese subjects before and after bariatric surgery. The effect of acute and chronic exercise was then assessed in 15 young healthy adults who performed intermittent sprint running sessions over an 8 week period. Results Tissue arrays demonstrated that in humans, the FNDC5 gene is predominantly expressed in muscle. Circulating irisin was detected in the serum or plasma of all subjects studied, whereas circulating FNDC5 was detected in only a distinct minority of the subjects. Cross-sectional studies revealed that circulating irisin levels were positively correlated with biceps circumference (used as a surrogate marker of muscle mass herein), BMI, glucose, ghrelin, and IGF-1. In contrast, irisin levels were negatively correlated with age, insulin, cholesterol, and adiponectin levels, indicating a possible compensatory role of irisin in metabolic regulation. Multivariate regression analysis revealed that biceps circumference was the strongest predictor of circulating irisin levels underlying the association between irisin and metabolic factors in humans at baseline. Both muscle FNDC5 mRNA levels and circulating irisin levels were significantly downregulated 6 months after bariatric surgery. Circulating irisin levels were significantly upregulated 30 min after acute exercise and were correlated mainly with ATP levels and secondarily with metabolites related to glycolysis and lipolysis in muscle. Conclusions Similar to mice, the FNDC5 gene is expressed in human muscle. Age and muscle mass are the primary predictors of circulating irisin, with young male athletes having several fold higher irisin levels than middle-aged obese women. Circulating irisin levels increase in response to acute exercise whereas muscle FNDC5 mRNA and circulating irisin levels decrease after surgically induced weight loss in paral...

Despite the differences in basal irisin levels, exercise-induced irisin secretion is independent of age or fitness level. Increased irisin can directly modulate muscle metabolism through AMP kinase activation.

Summary Objectives Vitamin D deficiency (VDD) has been proposed to play a role in Coronavirus Disease 2019 (COVID‐19) pathophysiology. We aim to evaluate our implementation of a local protocol for treatment of VDD among patients hospitalized for COVID‐19; to assess the prevalence of VDD among COVID‐19 inpatients, and examine potential associations with disease severity and fatality. Design and Participants We conducted a retrospective interim audit of a local clinical care pathway for 134 inpatients with COVID‐19. Prevalence of VDD, compliance with local treatment protocol and relationship of baseline serum 25(OH)D with markers of COVID‐19 severity and fatality were analysed. Results 55.8% of eligible patients received Colecalciferol replacement, albeit not all according to the suggested protocol. Patients admitted to ITU were younger than those managed on medical wards (61.1 years ± 11.8 vs. 76.4 years ± 14.9, respectively, p<0.001), with greater prevalence of hypertension, higher baseline respiratory rate, National Early Warning Score‐2 and C‐Reactive protein level. While mean serum 25(OH)D levels were comparable (p=0.3), only 19% of ITU patients had 25(OH)D levels greater than 50 nmol/L vs. 39.1% of non‐ITU patients (p=0.02). However, there was no association with fatality, potentially due to small sample size and prompt diagnosis and treatment of VDD. Conclusions Higher prevalence of VDD was observed in patients requiring ITU admission compared to patients managed on medical wards. Larger prospective studies and/or clinical trials are needed to validate and extend our observations.