Abstract
The health scourge imposed on humanity by the COVID-19 pandemic seems not to recede. This fact warrants refined and novel ideas analyzing different aspects of the illness. One such aspect is related to the observation that most COVID-19 casualties were older males, a tendency also noticed in the epidemics of SARS-CoV in 2003 and the Middle East respiratory syndrome in 2012. This gender-related difference in the COVID-19 death toll might be directly involved with testosterone (TEST) and its plasmatic concentration in men. TEST has been demonstrated to provide men with anti-inflammatory and immunological advantages. As the plasmatic concentration of this androgen decreases with age, the health benefit it confers also diminishes. Low plasmatic levels of TEST can be determinant in the infection’s outcome and might be related to a dysfunctional cell Ca2+ homeostasis. Not only does TEST modulate the activity of diverse proteins that regulate cellular calcium concentrations, but these proteins have also been proven to be necessary for the replication of many viruses. Therefore, we discuss herein how TEST regulates different Ca2+-handling proteins in healthy tissues and propose how low TEST concentrations might facilitate the replication of the SARS-CoV-2 virus through the lack of modulation of the mechanisms that regulate intracellular Ca2+ concentrations.
Highlights
Despite the restrictive measures and massive vaccination campaigns, the number of people affected by the current COVID-19 pandemic is growing daily
Interacts with various essential regulatory proteins that maintain [Ca2+]i homeostasis. Even though this androgen’s physiological role has not been fully elucidated, some evidence hints at its detrimental role in COVID-19 patients warranting further research to understand better the possible effects that TEST could have on the infection and repl2icoaf-20 tion of the SARS-CoV-2 virus
Even though this androgen’s physiological role has not been fully elucidated, some evidence hints at its detrimental role in COVID-19 patients warranting further research to understand better the possible effects that TEST could have on the infection and replication of the SARS-CoV-2 virus
Summary
Despite the restrictive measures (i.e., isolation, social distancing) and massive vaccination campaigns, the number of people affected by the current COVID-19 pandemic is growing daily. When comparing young adult men with elderly patients, when TEST concentrations are progressively decreasing, we observe a greater severity and mortality; the above mentioned TEST immunosuppressive effects in COVID-19 patients might not be justified In this context, we propose that low plasmatic levels of TEST can be determinant in the infection’s outcome and the replication of the SARS-CoV-2 virus through the modulation of the mechanisms that regulate intracellular Ca2+ concentrations ([Ca2+]i) in host cells. A wide range of evidence from different cell types points out that TEST interacts with various essential regulatory proteins that maintain [Ca2+]i homeostasis Even though this androgen’s physiological role has not been fully elucidated, some evidence hints at its detrimental role in COVID-19 patients warranting further research to understand better the possible effects that TEST could have on the infection and replication of the SARS-CoV-2 virus. CalTcihuemcaSlcigiunmaliinogn (Ca2+) is a versatile second messenger in all cell types and regulates mulTtihpelecsailgcinuamlinigonpr(Cocae2s+s)eiss raevsperosnastiblelesefocornedssmenetsiasel ncgelelrfiunnacltliocnelsl. tTyhpeesparoncdesresegsuliat tceasn mreugltuiplalteesaigrentailmineg-dperpoecnesdseenstr: einspmonicsriobsle cfonr des,senxoticayl tcoeslilsfiusngcetinoenrsa.teTdh,einprmoiclelissseecsoint dcsa,nit reingiutilaatteesacroenttirmacet-idoenp, eannddeinnt:mininmutiecsroosrechoonudrs, eitxocryigtionsaisteiss egveennetrsa,tseudc,hinams fiellritsieliczoantidosn,, itpirnoiltiifaetreasticoonn,ttrraacntisocnri,patniodni,ngmenienuretegsuolartihoonu, rasn, dit aopriogpintoastiess[e3v3e,3n4t]s., Usuncdhearsrefesrtitnilgizcaotinodni,ptriolnifse, rcaetlilosnm, tarianntsacinripctyitoons,ogliecnCear2e+gcuolnactieonnt,raatniodnasproapntgoisnigs [f3r3o,m34]1.0U0 nndMertore1st5i0ngnMcon[3d5i-]; tieoxnqsu, icseitlelslymreaginutlaaitnedcymtoescohlaicniCsma2s+mcoanincteanintrathtieoenqsurialinbgrinugmfbroemtw1e0en0 nthMe etxotr1a5c0elnluMla[r3m5]i;elxiequui(sCitae2l+ycorengcuenlattreadtiomnesc~h2anmisMm)sanmdaintaraincetlhluelaerqCuail2i+bsrtiourmesb(eCtaw2+eceonntcheenterxatrioancesl~lu5l–a1r0 mmilΜie)u[(3C6,a327+].cTonhceehnotrmateiosntsas~is imn MCa)2a+ nsidgninatlrinacgeilsludlaerteCrma2i+nesdtobreys a(Cbaa2l+anccoenbcentwtreaetnionthse ~p5–ro1t0eminMs t)h[a3t6i,n3c7r]e. aTsheeChao2+mweiotshtiansitshiencCytao2p+lsaisgmna: lLin-VgDisCdCe,teSrOmCinCesd, rbeyceapbtoarla-onpceerbaetetwdeCean2+ thcheapnrnoetelsin(sRtOhaCtCins)c,reNaas+e/CCaa22++ewxcihthainngtehreicnyittosprleavsmer:seL-fVorDmCC(N, SCOXCRECV)s,, IrPe3cerpectoerp-toopre(rIaPt3eRd), Ca2+ channels (ROCCs), Na+/Ca2+ exchanger in its reverse form (NCXREV), IP3 receptor (IP3R), and ryanodine receptor (RyR) and proteins that decrease concentrations to basal levels: plasma membrane Ca2+ ATPase (PMCA), sarcoplasmic reticulum Ca2+ ATPase (SERCA), Na+/Ca2+ exchanger (NCX) and the mitochondrial uniporter [36,38,39,40] Importantly, alterations in this Ca2+-dependent homeostatic mechanism might participate in various pathophysiological conditions, including viral infections [33]
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