Detrimental Effects of Malaria, Toxoplasmosis, Leishmaniosis and Chagas Disease on Cardiac and Skeletal Muscles

M. T. Marrelli et al. Medical Research Archives vol 8 issue 9. Medical Research Archives

REVIEW ARTICLE

Detrimental effects of malaria, toxoplasmosis, leishmaniosis and Chagas disease on cardiac and skeletal muscles

Authors Mauro Toledo Marrelli1,2,*, Matthew William Fiedler1, Claudia Biguetti1, and Marco Brotto1

Affiliations 1Bone-Muscle Research Center, https://www.uta.edu/conhi/research/bmrc/index.php College of Nursing & Health Innovation, University of Texas-Arlington, 411 S. Nedderman Drive, Arlington, TX 76019-0498, USA.

2Department of Epidemiology, School of Public Health, University of São Paulo, Avenida Dr. Arnaldo 715, São Paulo-SP, 01246-904, Brazil

*Correspondence Marco Brotto. E-mail: [email protected]

Abstract

The pathogenic mechanisms of several diseases triggered by protozoan parasites, such as the causative agents of Chagas disease, toxoplasmosis, leishmaniosis, and malaria, have demonstrated to cause direct detrimental effect on cardiac and skeletal muscle. These are amongst the most prevalent and epidemiologically relevant protozoan infections worldwide and infecting millions of people per year. As such, this review focuses on the current knowledge on the pathogenic mechanisms of these diseases on muscles. Case studies and original research addressing the mechanisms of action for direct and indirect damage to cardiac and skeletal muscle were analyzed and the main findings summarized. Importantly, all diseases reviewed here produce an intense inflammatory response, with the associated oxidative stress and pro-inflammatory cytokine production leading to or furthering these detrimental effects. Critically, the disruption of cardiac muscle function can lead to minor arrhythmias and even death, and skeletal muscle damage can result in homeostatic imbalances serving to further morbidity and mortality. Strategies for preventing complications and determining the effectiveness of interventions designed with antioxidant and anti-inflammatory molecules to minimize muscle injury and help the millions of people with these diseases are an urgent need.

Keywords: Skeletal muscle, cardiac muscle, protozoan parasites, inflammation, oxidative stress

M. T. Marrelli et al.Medical Research Archives vol 8 issue 9. September 2020 Page 2 of 17

Introduction combine several aspects that together can be largely detrimental to the musculoskeletal Mammalian muscle tissues are (MSK) system. We also interpret the MSK as divided into three types according to their buffering sentinel for the organism; at the function and morphology: skeletal, cardiac, expense of the MSK other organs can be and smooth. Skeletal muscle is the most preserved. abundant of the three forms of muscle in the Most of the pathogenesis caused by human body, consisting of long, striated, and intestinal protozoans, such as Giardia spp., multinucleated fibers (also called striated Entamoeba hystolitica, Balantidium spp., muscle myocytes) that align in a regular Cryptosporidium spp., Isospora spp., and pattern of fine red and white lines. This Cyclospora spp., induce diarrheas or appearance is distinct and conserved across dysenteries leading to electrolyte imbalance mammalian species (1). Cardiac muscle is and dehydration. Without proper treatment, also composed by striated myocytes, but severe electrolyte imbalances can cause loss consisting of mononucleated fibers, found of muscle mass with or without the loss of fat only in the heart, and responsible for the mass (7, 8). While some of this damage can circulation of blood throughout the body. be indirect, the generation of action potentials Although mononucleated, cardiac muscle to induce muscle contractions is fully cells can undergo hypertrophy with two or dependent on a tight electrolyte balance, and three nuclei. In cardiac muscle, two or more disturbances can severely affect muscle myocytes can attach laterally via function. Muscle weakness can develop, as desmosomes. The striated microscopic well as cramps and muscle contractures, appearance in both skeletal and cardiac which under certain conditions can lead to muscles is from the filaments of actin and rhabdomyolysis, a severe muscle damage myosin responsible for muscle contraction that can also damage the kidneys due to the (2). Myopathies, a general term used to release of myoglobin in the blood. In the describe diseases of muscle tissues dating same way, the pathogenic mechanisms of back to the mid 1800’s, negatively affects other protozoan parasites, such as Chagas muscle fiber function, leading to muscle pain, disease, toxoplasmosis, leishmaniasis, and weakness, and fatigue (3, 4). Muscle malaria, have been demonstrated to cause myopathies are either acquired or inherited. direct detrimental effect on the Acquired myopathies sub-classify in musculoskeletal and cardiovascular system inflammatory, toxic, infectious, and (Table 1). associated with systemic diseases. Inherited Due to the worldwide importance of myopathies are: muscular dystrophies, these protozoan parasites, this review is congenital myopathies, metabolic focused on the detrimental effects on skeletal myopathies, and mitochondrial myopathies. and cardiac muscle caused by the infection of (5). Infectious diseases caused by the protozoan parasites that result in serious microorganisms, such as viruses, bacteria, and highly prevalent diseases; Trypanosoma and parasites, may cause direct and/or cruzi (Chagas diseases), Leishmania spp. indirect damage in cardiac and skeletal (leishmaniasis), Toxoplasma gondii muscle resulting in myopathies (6). An (toxoplasmosis), and Plasmodium spp. important aspect of these infectious diseases (malaria). All but Plasmodium spp. have is the infecting component, their systemic been detected inside striated muscle fibers nature, pro-inflammatory properties, and the and directly affect striated muscle and induction of metabolic changes. They cardiac cells (Table 1). Although possess the intrinsic destructive capacity to

Plasmodium spp. has never been observed and toxoplasmosis, therefore, the results from infecting muscle cells, numerous reports animal models or in naturally infected have demonstrated that malaria infection can animals should be interpreted with caution. seriously affect skeletal and cardiac cells (9- Despite that limitation, the discussed studies 11). brought insights to the knowledge of the Of the four protozoan diseases we pathologies caused by these zoonotic focus on here, Chagas disease, leishmaniasis, parasites. Finally, Plasmodium spp. causes and toxoplasmosis are zoonosis; naturally malaria, a species-specific disease, with transmitted between animals and humans. murine malaria being the most used Leishmaniasis has shown completely experimental model used to compare effects different pathologies in canines when with human malaria. compared to humans, and to Chagas disease

Table 1. Main protozoan parasites that cause human diseases and relationship with damage effect in striated muscle fibers and other human organs or cells. Phylum Genera Diseases Detected inside Damage effect Infect other cells and striated muscle on muscles organs fibers Sarcomastigophora Leishmania Cutaneous, mucocutaneous and Yes Yes macrophages, skin, Visceral leishmaniasis, visceral organs Trypanosoma Chagas’ disease, sleeping Yes Yes macrophages, heart, sickness esophagi, intestine Giardia Diarrhea NE NDE small intestine Trichomonas Vaginitis NE NDE women lower genital tract, inside of the penis Entamoeba Dysentery, liver abscess NE NDE intestine, liver, lung, brain Dientamoeba Colitis NE NDE large intestine Naegleria and Encephalitis NE NDE central nervous system Acanthamoeba and cornea Apicomplexa Babesia Babesiosis NE NDE red blood cells Plasmodium Malaria No Yes hepatocytes and red blood cells Isospora Diarrhea NE NDE intestine Cryptosporidium Diarrhea NE NDE small intestine, heart Toxoplasma Toxoplasmosis Yes Yes central nervous system Ciliophora Balantidium Dysentery NE NDE large intestine NE: no evidence. NDE: no direct evidence.

1. Trypanosomatid parasites and their transmitted by tsetse flies), American effect in cardiac and skeletal muscles trypanosomiasis or Chagas disease (caused The three major human diseases by Trypanosoma cruzi and transmitted in caused by trypanosomatids are African endemic areas by triatomine bugs), and the trypanosomiasis or “sleeping sickness” three manifestations of leishmaniasis (caused by Trypanosoma brucei and diseases; cutaneous, mucocutaneous, and

Copyright 2020 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra M. T. Marrelli et al.Medical Research Archives vol 8 issue 9. September 2020 Page 4 of 17 visceral leishmaniasis (caused by various organs even in the absence of significant species of Leishmania transmitted by parasitemia (26). sandflies) (12). These vector-borne diseases Myotropic or non-myotropic strains affect humans and other mammals and are of T. cruzi may show different behavior when responsible for significant morbidity and in contact with muscle cells (27). The mortality worldwide. Other species of interaction of T .cruzi trypomastigotes from Trypanosoma and Leishmania infect a wide amyotropic strain (CL and Colombiana range of vertebrate hosts, all transmitted by strains) comparing to a macrophage tropic arthropods (13). Their pathogenic processes strain (Y strain) with mice myoblasts and can cause detrimental effects on skeletal and myotubes, showed that parasites from the cardiac muscle in vertebrates (14-19). myotropic strains were more infective to myoblasts than those from the 1.1. Trypanosoma cruzi and the Chagas macrophagotropic strain (16). Interestingly, diseases myoblasts infected with parasites from non- The prevalence of Trypanosoma cruzi myotropic strains are able to fuse with other is approximately 6-8 million persons infected and uninfected cells to form worldwide, although many experts in the myotubes. However, the process of fusion field believe this number is underestimated, was inhibited when the myoblasts were and approximately 10,000 die each year from infected with parasites from the myotropic Chagas disease complications (20). Around strains. Normal myogenic processes in 30% of people with Chagas disease develop murine cardiac cells were disrupted by serious complications (21). myotropic strains exclusively (18). The effect of T. cruzi parasites on Previous work by Báez et al. has skeletal and cardiac muscles has been provided building evidence that functional investigated for decades (16, 18). The high and structural alterations to mitochondria are genetic diversity of the Chagas disease responsible for chagasic cardiomyopathy parasite produces heterogeneous clinical (28-30). More recent studies from the same manifestations (22). This has been reflected group have extended this effect to murine in the differences observed in organ damage, skeletal muscle, observing disruptions in with evidence of organ or tissue tropism citrate synthase activity and cellular highly associated to the T. cruzi strain (23). respiration malfunction. All samples from The crucial importance of the autoimmune infected mice showed at least one structural response in the pathogenesis of cardiac abnormality related to mitochondrial enzyme Chagas was demonstrated by Wesley et al., malfunction, such as increased matrix where the analysis of T. cruzi kDNA formation or cristae disorganization (28). minicircle integration into the mammalian Acute and chronic Chagas disease can host genome was correlated to the levels of induce severe acute myositis, rapidly leading IgG antibodies reactive to host cardiac to the degeneration and necrosis of muscle proteins and interferon production, both fibers (31, 32). This significantly reduces influencing tissue inflammation (24). High skeletal muscle contractility and, in the early levels of pro-inflammatory cytokines is stages can be reversed by myogenic stem cell linked to cardiac damage (25). However, a activation (31, 33, 34). direct correlation between parasite load and Throughout the chronic phase, tissue damage is not entirely clear as there are cardiac tissue abnormalities present a variety descriptions of parasite-triggered of symptoms, ranging from slight autoimmunity that can indirectly damage electrocardiogram (EKG) alterations to

Copyright 2020 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra M. T. Marrelli et al.Medical Research Archives vol 8 issue 9. September 2020 Page 5 of 17 sudden cardiac death (SCD). Congestive knockout (KO) mice present higher heart failure (CHF) can also develop, parasitemia, reduced cardiac and skeletal presenting a myriad of complex healthcare muscle tissue inflammation, and lower conditions (35). Novaes et al. demonstrated survival rates compared to wild-type (WT) reductions in aerobic exercise tolerance in mice (42). infected rats (36-38). Despite this limitation, Emerging stem cell-based therapies comparisons between sedentary and provide an impactful advance in the aerobically active groups suggest that treatment of chronic-degenerative diseases. exercise may induce beneficial adaptations. Transplantation of bone marrow cells Active rats saw decreases in pro- (BMCs) can regenerate heart and skeletal inflammatory cytokines: interferon gamma muscle lesions caused by T. cruzi infection in (IFN-γ), tumor necrosis factor alpha (TNF- experimental models, potentially mitigating α), and IL-6. Parasitemia, tissue the damage caused by T. cruzi. This supports inflammation and fibrosis, and cell atrophy the potential benefits of stem cell-based markedly decreased while serum antioxidant therapy during the chronic phase of Chagas enzymes increased. This resulted in disease, drastically accelerating the natural decreased cardiac oxidative damage, limiting regeneration process (43), although such a contractile dysfunction(37, 38). Similar therapy modality is economically effects have been seen in humans, greatly challenging for most of the countries increasing cardiac functionality (39). impacted by these diseases. The suppression of cytokine signaling 2 (SOCS2) can regulate immune responses 1.2. Effects of Leishmaniasis infection in and may play a role in the pathogenesis of T. skeletal and cardiac muscles cruzi infection. Reductions in parasitemia The Leishmania genus represents and the expression of IFN-γ, TNF-α, SOCS1, more than 30 different species, some and SOCS3 were detected in SOCS2 infecting humans, causing a wide spectrum of knockout (KO) mouse cardiac muscle. An clinical manifestations classified into increase in the growth and formation of T cutaneous (CL), mucosal (ML) and visceral regulatory (Treg) cells with a decrease in leishmaniasis (VL). Estimates suggest that memory cells in infected SOCS2 KO mice between 10 and 50 million people are with T. cruzi has been reported, indicating infected with Leishmania spp. in 98 countries reductions in inflammation and parasitemia causing more than 1.5 million cases per year. in infected SOCS2-KO mice may be VL is the most serious and deadly form of secondary to the increases in Treg cells, this disease. Leishmaniasis is a serious suggesting another future therapeutic disease, killing an estimated 50,000 people in direction (40). 2010. This burden is not spread equally, with Surface carbohydrates have been only six countries reporting 90% of all VL associated with processes of cell recognition cases, and ten countries reporting 75% of all and surface markers also play a role in T. CL cases. (44). cruzi infection and in system response (41). Leishmania species can infect Galectin-1 (Gal-1) is an endogenous surface different tissues and organs of the host (26). glycoprotein expressed on the surface of The infection is initiated in macrophages, but human and murine cardiac cells that reduces other cell types can be infected, including both the likelihood of infection and apoptosis fibroblasts, dendritic cells, and muscle fibers. induced by T. cruzi. Infected humans and Leishmaniasis are among the main causes of rodents increase Gal-1 expression, and Gal-1 muscle lesions and muscle atrophy in canines

(14), the main domestic reservoir of the Turning towards muscle disease (45). Canines infected with performance, the plantaris, soleus, and Leishmania spp. have shown cardiac effects diaphragm muscles from L. donovani as well (15, 17, 19). Alves et al. showed infected hamsters showed both direct and cardiac and pulmonary alterations in both indirect effects on skeletal muscle symptomatic and asymptomatic canines with performance when comparing the effects of visceral leishmaniasis, caused by L. chagasi simple calorie restriction and chronic (15). Study cases of chronic myocarditis on leishmaniasis infection. Both scenarios canines naturally infected with L. chagasi produced similar reductions in body weight showed the development of cardiac muscle and muscle cross-sectional area. Caloric alterations with clinical and pathological restriction alone could explain the reductions consequences. Such involvement seems to be in muscle cross sectional areas and tetanic related to the tissue’s response to tension of the diaphragm and soleus muscles Leishmania, and not Leishmania itself (19). of the infected animals, suggesting Providing further evidence of nutritional interventions to offset some of immunological dysfunction, Silva-Almeida these deleterious effects (47). et al. demonstrated that a mouse strain Relative caloric reduction to muscle susceptible to Leishmania infection tissues may be a key piece of the pathogenic (BALB/c) showed a high number of infected mechanism (48). Leishmaniasis is known to macrophages among muscle fibers at the cause latent infections (49), whose agents onset of disease. Importantly, the major stay viable as inactive forms in adipose Leishmania infection susceptibility in tissue, adipose tissue-derived mesenchymal BALB/c mice strain is related to their genetic stem cells, and fibroblasts (50). Pre- background which favors/leads the adipocytes can develop macrophage-like development of a predominant Th2 type phagocytic characteristics (51), and when response, with the production of high levels dormancy is disturbed by an exogenic of IL10 and IL4 cytokines, and a defective stimulus, such as caloric restriction (e.g., expression of CXCR3 chemokine receptors dieting), Leishmania can migrate to other in T cells upon activation (46). These genetic sites, including muscle, in search of nutrients susceptibilities contribute to explain the large (48). non-healing lesions in BALB/c mice. On the Case reports on the detrimental other hand, C57Bl/6 and C3H.He strains effects of Leishmania parasites on human present favorable outcomes for Leishmania skeletal muscles in children document infection, because of their ability for marked loss of mass in posterior muscles, mounting a protective IL-12 induced Th1- suggesting that weakness accompanying type response. In the C3H.He Leishmania Leishmania infection results not only from resistant mouse strain, muscle fibers are loss of muscle mass, but also from the found mostly spared, though some impaired contractile performance of the parasitized macrophages were discovered remaining muscle (52, 53). A 1993 case (26). In line with the previous works, the report demonstrated the dangers of ignoring major pathophysiological effect of conflicting pathologic testing concerning Leishmania on the musculature appears to be leishmaniasis. A nine-year-old child with related with immunological alterations in fever and severe muscle dysfunction humans, rodents and canine hosts and as produced no antibodies against numerous infected macrophages were observed, likely bacterial, viral, or parasitic diseases. inflammatory (14, 15, 17, 19, 26, 45). However, serological testing for L. infantum

Copyright 2020 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra M. T. Marrelli et al.Medical Research Archives vol 8 issue 9. September 2020 Page 7 of 17 and L.donovani showed high circulating 2.1. Toxoplasmosis affecting skeletal and antibody levels. Leishmania amastigotes cardiac muscles were not found in bone-marrow aspirate. Toxoplasma gondii is one of the most Increased serum creatine kinase (CK) and medically relevant protozoan parasites, muscle biopsy findings confirmed myositis. affecting avian species, reptiles, amphibians, As bone-marrow smears were negative for and mammals. Toxoplasmosis is the most leishmania amastigotes, pathologists prevalent parasitic infection in humans, with incorrectly considered the serological an impressive infection rate of 25 to 30% in findings to be falsely positive. The child the world population (55). Although most started on prednisone and saw improvements toxoplasmosis infections are asymptomatic, in strength and pain within a week of infection can be devastating in treatment (53). immunosuppressed or immunocompromised Eight months later, the child was individuals (56). For example, toxoplasmosis readmitted to the hospital with return of is the most common secondary nervous symptoms and hepatosplenomegaly. VL was system infection in individuals with acquired confirmed by the presences of leishmania immune deficiency syndrome (AIDS) (57). amastigotes in bone-marrow smears. After Higher frequencies of muscle effects from T. correcting the treatment with pentavalent gondii have been found in persons with AIDS antimony derivative there was a significant with 0.5-4% of T. gondii and AIDS- improvement in hematological findings and diagnosed persons showing toxoplasma regression of hepatosplenomegaly occurred cysts, greater than those with T. gondii only. shortly thereafter (53). Despite the paucity of Muscular T. gondii involvement results in case reports, Leishmania spp. should be greater weakness, myalgias, and elevated considered as a possible cause of human CK, suggesting the need for muscular myositis, particularly when other etiologies biopsies for persons with AIDS in areas with are dismissed. endemic T. gondii activity (58). The bradyzoite stage primarily affects 2. Apicomplexa phyla brain and muscle tissue which, innately, have limited immune response capability (59). Apicomplexa is a taxonomic group of Toxoplasmic pneumonitis is responsible for protozoa of about 5,000 species, grouped on pulmonary complications related to AIDS the presence of an apical complex in the that can lead to septic shock (60, 61). sporozoite and merozoite stages (54). Many Myocarditis caused by T. gondii is a rare but species of this group cause severe diseases in serious complication that can result in SCD humans, such as babesiosis, malaria, (56, 62-65). Cardiac effects are more toxoplasmosis, and coccidiosis. Plasmodium pronounced in heart-transplant recipients; a spp. and Toxoplasma gondii are the main retrospective study found that of the 1.3% of apicomplexan protozoans that cause direct persons that developed T. gondii infections in and indirect detrimental effects on skeletal the post-operative period following and cardiac muscle. Numerous studies have transplantation, 50% died (66). demonstrated apicomplexan infection-related Gomes et al. investigated the skeletal and cardiac muscle damage which ramifications of T. gondii infection on will be discussed. myogenesis in a skeletal muscle model (67, 68). Macroscopically, infected myoblasts saw significant myogenic inhibition, increased infection risk, and a complete

Copyright 2020 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra M. T. Marrelli et al.Medical Research Archives vol 8 issue 9. September 2020 Page 8 of 17 inability to fuse into myotubes. In addition, made in the 2015-2017 period with new cadherin expression was down-regulated (67) infections and deaths stabilizing, and over 3.2 and intracellular lipid bodies increased, billion potentially exposed to malaria providing nutrient storage for T. gondii, worldwide (73). redirecting nutrients intended for the muscle Plasmodium parasites have never to itself (68). Towards myokines, infected been detected inside muscle fibers, preferring cells showed increased IL-12, IFN-γ, indirect damage related to their pathologic prostaglandin E2 (PGE2), and mechanisms. Although the most serious cyclooxygenase 2 (COX-2) (68). Chronic T. effects of malaria infection in skeletal and gondii infections present a life-long struggle cardiac muscles have been related to the with systemic inflammation, gradually species P. falciparum, other Plasmodium worsening as parasitic cysts develop in the species, including the human P. vivax, have brain and skeletal muscle (69). This been shown to damage heart and muscles eventually leads to complex myositis and (74-77). In the case of P. falciparum, the bulk associated muscle damage from the chronic, of systemic damage derives from the extensive accumulation of pro-inflammatory agglutination and subsequent macrophages (70). One therapy option is the microvasculature sequestration of reduction of regulatory T cells during erythrocytes leading to hypoxia (77), rather infection, rescuing macrophage homeostasis than any currently recognized effect on the and allowing skeletal muscle regeneration. erythrocytes themselves (10, 78). The This suggests that a significant portion of the resulting skeletal muscle necrosis and related muscular symptoms of T. gondii infection rhabdomyolysis has been reported in persons directly results from the person’s own with severe P. falciparum (10, 79, 80). This immune response (71). effect can be detected via increased CK Muscle is not defenseless, however. levels, indicating an increase in skeletal and SkMCs infected with IFN-γ and/or TNF-α- cardiac muscle damage (79, 81). activated T. gondii triggers the expression of These effects extend to protein- and inducible nitric oxide synthase (iNOS), functional-level testing as well. Infected rat leading to elevated intracellular nitric oxide muscle showed lower protein transcription (NO) levels. This significantly inhibits the and protein levels when compared to non- replication of intracellular T. gondii parasites, muscular tissue and non-infected rats (82). as seen by the increase in immune-related Our group demonstrated this effect with P. GTPases (IRG) within parasitic vacuoles. berghei infected mice, halving extensor This, ultimately, does not prevent tachyzoite- digitorum longus (EDL) and soleus (SOL) bradyzoite transformation and can only slow, muscle contractile force and significantly not stop, the progression of the infection (72). impaired fatigue recovery capacity following exercise (83). These effects were associated 2.2. Effect of Plasmodium spp. infection in with the significant decrease in contractile skeletal and cardiac muscles proteins (e.g., myosin and troponin) in the Malaria is one of the most prevalent muscle fibers of infected rodents, and severe protozoan diseases worldwide. corroborating with prior findings of Approximately 219 million cases and detectable serum contractile proteins 435,000 deaths were reported in the year following plasmodium infection (79, 81, 84, 2017, with children and pregnant women 85). Elevated muscle protein levels were remaining the most affected group. observed in the plasma of children with Disappointingly, little if any progress was cerebral malaria, indicating muscle-specific

Copyright 2020 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra M. T. Marrelli et al.Medical Research Archives vol 8 issue 9. September 2020 Page 9 of 17 proteins in plasma as a potential indicator of Glycosyl phosphatidylinositol (GPI) has advanced malaria (86). many functions, including acting as a toxin Case studies have demonstrated during malaria falciparum pathogenesis. numerous P. vivax infection-related cardiac Cardiomyocytes treated with purified complications including tachycardias, falciparum GPI showed upregulated genes arrhythmias, and CHF (87-89). A decent part related to apoptosis and myocardial damage. of these effects may stem directly from This effect has also been seen in human case antimalarial therapies themselves. EKG studies (95). reports from Plasmodium infected persons have demonstrated cardiac arrhythmias as a 3. Conclusions leading cause of SCD in severe infection The parasitic diseases discussed here cases (87, 89). P. chabaudi, P.vinckei, P. affect human muscles both directly and petteri, and P. yoeliinigeriensis produced indirectly. While only Leishmania spp., irreversible lesions on the heart and other Trypanosoma cruzi, and Toxoplasma gondii organs following acute and chronic infection have been detected within muscle fibers, in mice (84). Humanized Balb/c mice Plasmodium spp. causes indirect damage to infected with P. falciparum from human muscle tissue. Other protozoan parasites (not blood revealed high levels of peripheral discussed in this review) operate indirectly parasitemia and the deaths of 10 out of 25 and in more discreet ways, such as Giardia inoculated mice. Post-mortem examination spp., Cryptosporidium spp., and Balantidium revealed extensive cardiac sequestration and spp. (Table 1), causing diarrhea and inflammatory mediator presence (88). dysentery, leading to dehydration and Several serum biomarkers can be malnutrition sufficient to inflict loss of used to measure the severity of plasmodium muscle mass. The direct and indirect effects infection-induced myocardial injury and of protozoan infections on muscles are necrosis. N-terminal pro-brain natriuretic summarized in Figure 1. Direct damage can peptide (NT-proBNP) and heart-type fatty come from resultant inflammation, such as acid-binding protein (H-FABP) were with Leishmaniasis infection, or from the significantly elevated in complicated, but not pathologic mechanism of the parasite itself, uncomplicated, plasmodium cases in a case- seen in the structural mitochondrion changes control study with 63 participants (90). seen in Chagasic infections. None of the Similar results were seen in a separate study diseases discussed here limit themselves to with 400 African children with mild-to- just the muscle; Plasmodium spp. invades severe P. falciparum infection. Significantly hepatocytes and erythrocytes, Trypanosoma elevated levels of myoglobin and CK were cruzi the heart, esophagus, intestines, and seen in children with severe- and fatal-stage macrophages. infection respectively (91). The diseases caused by the protozoan The release of Troponin T, the most parasites reviewed here induce an intense sensitive and selective biomarker for inflammatory response, with oxidative stress myocardial damage (92), occurs when the and elevated production of pro-inflammatory myocardium is damaged by a variety of molecules (cytokines and lipid mediators), conditions, such as necrotic tissue injury (93, leading to detrimental effects on cardiac and 94). Analysis of sera samples from P. skeletal muscles. It is noteworthy that falciparum persons showed that the pathologies caused by these protozoan myocardia damage detected by high parasites may also affect the activity of the Troponin T levels is a rare event (92). infected vertebrate, potentially exacerbating

Copyright 2020 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra M. T. Marrelli et al.Medical Research Archives vol 8 issue 9. September 2020 Page 10 of 17 the loss of muscle mass and function. Further antioxidant and/or anti-inflammatory study into the effects of parasitic diseases on molecules to minimize muscle injury and vertebrate hosts will advance efforts to find help the millions of people with these additional therapies and care strategies, with diseases.

Figure 1. Proposed schematic model of the direct and indirect pathogenic effects of protozoan infections on cardiac and skeletal muscles. After the host infection by protozoan parasite [e.g. Trypanosoma cruzi (Chagas disase), Leishmania spp. (leishmaniasis), Toxoplasma gondii (toxoplasmosis), and Plasmodium spp (malaria)]. These protozoans can induce an intense inflammatory response, with the associated oxidative stress and pro-inflammatory cytokine production leading the establishment of positive feedback loop. Some species of protozoans (e.g. Leishmania spp.), can infect different tissues and cells, such as macrophages, but muscle fibers can also be infected (eg. leishmaniasis and Chagas). Infected macrophages can release more toxic substances to skeletal muscles. Reduction in caloric intake associated to these pathogens also contributes to decreased protein synthesis, delayed healing and muscle atrophy. In cases of severe myosistis (as observed in Chagas disease), there is rapid degeneration and necrosis of muscle fibers, which significantly reduces skeletal muscle contractility. In the magnified representation of infected muscles, the fibers are morphologically equivalent to cardiomyocytes, but the representation of pathological mechanisms is considered for both, skeletal and cardiac muscles.

Funding Kidney and NIDDK-R01DK119066; the CB, MM, MF, MB are supported by NIH George W. and Hazel M. Jay and Evanston Grants: National Institutes of Aging (NIA) 2- Research Endowments (MB), and the UTA PO1AG039355; NIA-R01AG056504, NIA- College of Nursing & Health Innovation R01AG060341; National Institutes of Bone-Muscle Research Center Neurological Disorders and Stroke (NINDS) (https://www.uta.edu/conhi/research/bmrc/in 2-R01NS105621; National Institutes of dex.php). Diabetes, Digestive, and Kidney Diseases

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