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 Copyright 2020 KEI Journals. All Rights Reserved 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 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 3 of 17 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