Irisin Produced During Exercising Can Prevent COVID-19 Disease Severity By Modulating Host Genes


A study conducted last year by Brazilian researchers from São Paulo State University (UNESP) is once again getting revived by various research groups and a few clinical trials are expected to start soon based on those earlier significant findings.

The study team then had found that the hormone Irisin produced during exercising can prevent COVID-19 disease severity by modulating host genes.

The study findings also illustrate why it is important for all during the COVID-19 pandemic to also get the right amounts of exercise in order to prevent COVID-19 disease severity.
Obesity patients are more susceptible to develop COVID-19 severe outcome due to the role of angiotensin-converting enzyme 2 (ACE2) in the viral infection. ACE2 is regulated in the human cells by different genes associated with increased (TLR3, HAT1, HDAC2, KDM5B, SIRT1, RAB1A, FURIN and ADAM10) or decreased (TRIB3) virus replication.
RNA-seq data revealed 14857 genes expressed in human subcutaneous adipocytes, including genes mentioned above.
Importantly Irisin treatment increased by 3-fold the levels of TRIB3 transcript and decreased the levels of other genes.
The decrease in FURIN and ADAM10 expression enriched diverse biological processes, including extracellular structure organization.
The study findings involving human subcutaneous adipocytes cell culture indicate a positive effect of irisin on the expression of multiple genes related to viral infection by SARS-CoV-2; furthermore, translatable for other tissues and organs targeted by the novel coronavirus and present, thus, promising approaches for the treatment of

The study findings were published in the peer reviewed journal: Molecular and Cellular Endocrinology By Science Direct. (Elsevier)
The study findings suggest that irisin, a hormone secreted from muscles in response to exercise, could have a therapeutic effect on COVID-19 patients.
Upon analyzing adipose cell gene expression, the study team found that irisin modulated genes associated with replication of the novel coronavirus SARS-CoV-2 in human cells.
The study findings were based on analysis of the transcriptome (all RNAs produced by genes) of adipose cells not infected by SARS-CoV-2 and treated with irisin.
Dr Miriane de Oliveira, researcher, UNESP’s Medical School in Botucatu, São Paulo told Thailand Medical News, “The study team compared data for genes important in COVID-19 with the transcriptomic data to make correlations. The results offer a clue in the search for treatment of the disease during the emergency caused by the pandemic. It must be stressed that our findings are preliminary and merely suggest that irisin could have therapeutic potential in cases of COVID-19. Further research can pick up from here to see whether irisin’s effects o n patients with the disease are indeed beneficial.”
The study data were produced by Oliveira in postdoctoral research supported by FAPESP and focusing on the action of irisin and thyroid hormones in adipocytes.
Importantly the utilization of sequencing techniques enabled the study team to identify 14,857 genes expressed in a subcutaneous adipose cell line. They observed alterations in gene expression when cells were treated with irisin.
The study team decided to investigate the possible effects of irisin on genes associated with the replication of SARS-CoV-2. From data cross tabulation, the tam discovered tha the treatment of adipocytes with irisin reduced the expression of the genes TLR#, HAT1, HDAC2, KDM5B, SIRt1, RAB1A, FURIN and ADAM10, which in turn regulate ACE-2, a key gene for viral replication because it encodes the protein to which the novel coronavirus binds in order to invade human cells.
Interestingly it also found that irisin tripled levels of transcription of the gene TRIB3. Previous research has demonstrated the importance of maintaining expression of TRIB3. In fact, expression of TRIB3 is frequently diminished in older people, a factor that may be linked to augmented replication of SARS-CoV-2 and a higher risk of COVID-19 in this segment of the population.
Dr Oliveira further added, “A third important point is the finding by other research groups that adipose tissue appears to serve as a repository for the virus. This helps explain the higher risk of developing severe forms of the disease for individuals with obesity. In addition, obese people tend to have lower levels of irisin and higher levels of the receptor molecule used by the virus than non-obese people.”
The hormone produced endogenously during continuous exercise, irisin is known to be involved in the browning of adipose tissue. White fat stores energy in the form of triglycerides and lipids and can become inflamed. Brown fat breaks down blood sugar and fat molecules to create heat and help maintain body temperature.
Hence, irisin is part of a calorie-burning process that can help treat metabolic disorders such as obesity. It is also known to modulate the activity of macrophages, which are immune cells that can release cytokines and trigger inflammation.
Dr Oliveira’s study is an example of how managing data obtained in basic research can lay the foundation for other discoveries and research.
Dr Oliveira’s added, “We began with a comparative analysis of the action of irisin and thyroid hormones in moderating fat accumulation and modulating genes in adipose cells. The study produced a large amount of data, and with the advent of the pandemic and the discovery by other research groups of genes associated with replication of SARS-CoV-2, we decided to use our database to investigate how irisin and thyroid hormones may influence the disease.”
The initial study set out to discover how these hormones perform their thermogenic role in reducing adipose tissue and generating energy in adipocytes.
Dr Oliveira said, “We did this by means of transcriptomics to identify the genes affected by the hormones in question, and our findings served as a basis for the study relating to COVID-19.”
The research findings showed that irisin not only moderates fat accumulation but also stimulates the expression of uncoupling protein 1 (UCP1), releasing heat and reducing fat deposits. Increased levels of UCP1 are compatible with decreased DNA damage and oxidative stress.
Armed with a more detailed understanding of the role played by irisin in obesity and possibly in COVID-19, the research group will now analyze its effect on cells infected with SARS-CoV-2.
Dr Oliveira concluded, “The aim is to take another step in this line of research and determine whether the results obtained in our bioinformatics investigation can be confirmed in a three-dimensional adipose cell culture model. We want to understand how irisin modulates the genes associated with SARS-CoV-2 replication.”

Irisin is a newly discovered myokine: proteolytic fibronectin type III domain containing 5 (FNDC5)-cleaved product. It induces browning of subcutaneous adipose tissues via elevation of uncoupling protein 1 and leads to thermogenesis and metabolic improvement (Bostrom et al., 2012).

Circulating levels of irisin increase transiently during acute exercise, and irisin concentrations are positively correlated with the intensity of exercise (Bostrom et al., 2012; Huh et al., 2014a; Huh and Mantzoros, 2015). However, such an effect was less pronounced in previous studies. Some studies failed to confirm the increase in irisin levels after chronic training (Huh et al., 2014b; Kraemer et al., 2014; Singhal et al., 2014). Irisin has been shown to increase temporarily after exercise, but not sustained in the long term (Huh et al., 2014b; Kraemer et al., 2014; Singhal et al., 2014).

Samy et al. (2015), recently reported that irisin concentration was related to oxidative stress and muscle damage, and suggested that unlike chronic exercise, acute exercise may increase oxidative stress significantly, resulting in irisin secretion from the muscle. However, whether different types of oxidative stress contribute to higher levels of irisin are unknown.

The aim of the present study is to evaluate whether heat stimulation-induced hyperthermia can increase circulating irisin levels after half-body immersion in hot water. High temperatures lead to oxidative stress (Portner, 2001; Portner and Knust, 2007) and elicit whole-body responses, involving skeletal and cardiac muscle tissues. In addition to irisin, we also analyzed blood creatine kinase (CK) and lactate dehydrogenase (LDH) levels as indicators of heat stimulation-induced oxidative damage.

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