key: cord-331428-6pvr2vew
authors: Heffernan, Kevin S.; Ranadive, Sushant; Jae, Sae Young
title: Exercise as medicine for COVID-19: on PPAR with emerging pharmacotherapy
date: 2020-08-17
journal: Med Hypotheses
DOI: 10.1016/j.mehy.2020.110197
sha: 
doc_id: 331428
cord_uid: 6pvr2vew

Coronavirus disease 2019 (COVID-19) may have a metabolic origin given strong links with risk factors such as lipids and glucose and co-morbidities such as obesity and type 2 diabetes mellitus. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein mediates viral cellular entry via the ACE2 receptor. The cytoplasmic tail of this spike protein is heavily palmitoylated. Emerging studies suggest that SARS-CoV-2 alters lipid metabolism in the lung epithelial cells by modulating peroxisome proliferator-activated receptor alpha (PPARα), possibly contributing to lipotoxicity, inflammation and untoward respiratory effects. Disruption of this process may affect palmitoylation of SARS-CoV spike protein and thus infectivity and viral assembly. COVID-19 is also increasingly being recognized as a vascular disease, with several studies noting prominent systemic endothelial dysfunction. The pathogenesis of endothelial dysfunction may also be linked to COVID-19-mediated metabolic and inflammatory effects. Herein, exercise will be compared to fenofibrate as a possible therapeutic strategy to bolster resilience against (and help manage recovery from) COVID-19. This paper will explore the hypothesis that exercise may be a useful adjuvant in a setting of COVID-19 management/rehabilitation due to its effects on PPARα and vascular endothelial function.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) currently shows no sign of disappearing on its own. Globally, Coronavirus disease 2019 (COVID-19) cases have surpassed 19 million, contributing to over 700,000 deaths. In the United States, the CDC projects that COVID-19 will be a top 10 leading cause of death for the year 2020. While we all eagerly await the development of a vaccine, scientists and clinicians have begun exploring "off-label" use of various drugs with that hope that strategic repurposing may help manage and treat COVID-19.(1) Fenofibrate (a peroxisome proliferator-activated receptor alpha agonist) is one such medication that holds promise given its favorable effects on inflammation and endothelial function. (1) Herein, exercise will be compared to fenofibrate as a possible therapeutic strategy to bolster resilience against (and help manage recovery from) COVID- 19 . This paper will explore the hypothesis that exercise may be a useful adjuvant in a setting of COVID-19 management/rehabilitation due to its effects on PPAR and vascular endothelial function.

COVID-19 progression has been suggested to have a metabolic origin given that elevated glucose and lipid levels are risk factors. The SARS-CoV-2 spike protein mediates viral cellular entry via the ACE2 receptor (please see our previous paper on the possible role of exercise as a mediator of ACE2). (2) The cytoplasmic tail of this spike protein is heavily palmitoylated (i.e. a 16 carbon fatty acid chain is added to palmitate), a common posttranslational modification that increases the hydrophobic nature of a protein. (3) Emerging studies suggest that SARS-CoV-2 alters lipid metabolism in the lung epithelial cells by modulating PPAR, possibly contributing to lipotoxicity and untoward respiratory effects. (4) PPAR belongs to the nuclear receptor (NR) family and is considered a key transcriptional factor that regulates lipid metabolism. PPARα is constitutively expressed in the lung. Not surprisingly, alveolar epithelial cells have been shown to conduct fatty acid oxidation, a function that serves a critical role in maintaining optimal lung function.(5) Disruption of this process may affect palmitoylation of SARS-CoV spike protein and thus infectivity and viral assembly. (3, 4) In response to pulmonary inflammation induced by lipopolysaccharide (LPS) or TNF, PPAR mRNA in the lung can be reduced by 50-60%. likely leads to inflammation and cytokine production (i.e. cytokine storm syndrome), reduction of nitric oxide and impaired vascular reactivity. Alterations in pulmonary vascular reactivity may affect gas exchange (i.e. alveolar-capillary barrier disruption) and be partially responsible for ventilation-perfusion mismatches and hypoxemia seen with COVID-19. (11) As alluded to previously, PPAR-activation has anti-inflammatory effects mainly achieved via transrepression, a process whereby pro-inflammatory genes are downregulated.

As such, use of the PPAR agonists may serve a useful therapeutic role by helping to reverse the inflammatory and metabolic changes induces by SARS-CoV-2. A recent study by Ehrlich et Much of the research to date on PPARs and exercise has focused on modulation of other isoforms (namely PPAR but also PPARδ/β) or key co-regulator/co-activators (e.g. peroxisome proliferator-activated receptor γ 1α, PGC-1α) in skeletal muscle. PPAR is expressed in cardiac myocytes, hepatocytes, enterocytes, lymphocytes, monocytes, adipocytes, smooth muscle cells, and as alluded to previously endothelial cells and epithelial cells. As such, PPAR plays an important role for systemic metabolic processes (heart, kidney, central nervous system, bone, intestines, pancreas, liver, lung). While PPAR is responsible for synthesis and storage Although studies have yet to explore the effect of exercise on PPAR in the lung, it is reasonable to speculate that mechanisms responsible for transcriptional changes in the heart and skeletal muscle would be similar in the lung. That is, the lung as a target organ is essential for mounting an optimal exercise response and delivering oxygen rich blood to the working skeletal muscle (i.e. cardio-respiratory fitness). The classic Karlman Wasserman "gear wheel model" describes the integrated exercise response as linking mitochondria, skeletal muscle, heart-blood (circulatory system) and lungs as inter-connected cogs. Increases in mechanical and metabolic factors that govern changes in PPAR in the heart and skeletal muscle may spill over to the respiratory system to ensure a concerted effort to match metabolic demand with cardio-respiratory supply. That habitual exercise training can modulate PPARα in the lung remains, at this time, a hypothesis. Conversely, there may be some redundancy between PPARα and PPARδ/β such that PPARδ/β can compensate for reductions PPARα and this may be target organ specific and differentially affected by exercise. (42) Empirical data will be needed to support (or refute) our hypothesis. Given the known effect of COVID-19 on the heart as an incendiary for cardiac damage, (43, 44) We have no conflicts of interest to disclose.

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Acknowledgements. We wish to thank Sara Mascone for her assistance creating Figure 1 .Conflicts of Interest: none to disclose
