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Do healthy muscles fight infections too?

It has been repeatedly reported that physical exercises are beneficial for health and also for improving the body’s ability to fight infections. However, exactly how exercising helps improve immunity against infections is still a mystery. The immune system which consists of both innate and acquired mechanisms protects the body from invading pathogens (infectious agents). The innate (native) immunity is the first line of defence post exposure to infection. Subsequently, the more complex and potent acquired (adapted) immune responses take over. In the Indian subcontinent, we are no strangers to infections, having been exposed to an ever increasing range of infectious diseases and related health concerns. Can exercising help build good muscles which then in turn are better at fighting infection?

Researchers at the Indian Institute of Science, Bangalore, have now investigated whether the muscles themselves play a key role in killing pathogens or do they rely on resident immune cells (like macrophages) to fight the infection. They used the fruit flies (Drosophila) and zebrafish as model systems and have studied the ability of skeletal muscle cells to initiate innate immune responses upon experimentally introducing bacterial infection.

Why were flies chosen to study innate immune reactions in muscles? “Drosophila has been used as a model for studying many human diseases and immune mechanisms. Drosophila does not have acquired immune system like higher vertebrates so it serves as a good model to dissect the innate immune pathway. In fact, studies in Drosophila were responsible for identifying major pathways of innate immunity, for which Prof. Hoffman was awarded the Nobel Prize”, explains Dr. Nongthomba of IISc, lead member of this study team.

Acquired immunity is an evolutionarily recent acquisition and is found only in vertebrates (animals with a backbone). In organisms like the fruit fly, which lack acquired immunity, the innate immunity is very important for fighting off infections. Interestingly, studies have reported that several components and pathways of innate immunity are conserved throughout evolution from Drosophila to vertebrates. Many genetic and molecular studies have revealed striking similarities between the innate immune system of flies and mammals. Two such examples of conserved innate immune mechanisms are the Toll signalling pathway and immune deficiency (Imd) pathway. These pathways are majorly involved in the production of anti-microbial peptides (AMPs), short chains of amino acids, against the invading pathogen.

The present study shows that muscles are capable of producing these AMPs which kill pathogens. This was demonstrated by marked increase in levels of AMPs seen in skeletal muscles (indirect flight muscles) of adult flies in response to deliberate infection. Next, researchers genetically disrupted the Toll and Imd pathways in flies and found that there was no increase in levels of AMPs post infection and the flies were more susceptible to the infection as well. This indicates that muscles produced the AMPs via initiation of these signalling pathways and this is important for the fly to be able to resist the infection and survive. This study also mentions that muscles induce the production of AMPs in response to the rise in the levels of reactive oxygen species (ROS) caused by the pathogens during infection. It is this attribute that perhaps make muscles ideal immune responsive tissues.

Using different fly strains carrying different genetic mutations, this study also illustrates that it may be majorly the healthy skeletal muscles that is directly involved in countering infections. Mutant flies with severely damaged flight and jump (i.e. mainly skeletal) muscles did not survive as well as flies with fundamental gene mutations resulting in overall abnormal muscles (including heart muscle). Also, the susceptibility of mutant flies to infection seems to be positively co-related with the degree of defect in their indirect flight muscles (skeletal muscles). The vulnerability of the mutant flies to infection was not directly because of abnormality in flight muscles, since the mutants were found comparable to normal flies with regards to walking, climbing, food uptake, etc.; but rather because the capacity of the muscles to produce AMPs was reduced in the mutants. In addition, the chances that survival is influenced by underlying genetics were nullified by the use of mutant fly strains from different genetic backgrounds. Collectively, these findings emphasized the importance of maintaining optimum flight muscle (skeletal muscle) physiology for survival of flies during infection.

Similar experiments performed in zebrafish trunk muscles prove that these mechanisms are conserved in vertebrates and that skeletal muscles sense and respond to infection in vertebrates too. Other studies have reported increased levels of an AMP, Hepcidin in mice muscle cells following bacterial infection. This was confirmed in present study as well, where increase in levels of Hepcidin was observed in zebrafish trunk muscles following experimentally induced bacterial infection.

Regular exercises are known to increase muscle mass, improve function and enhance immunity. With this study, it is now proven that not only does having healthy muscles boost general immunity but also contributes towards direct immune response by the skeletal muscles. On the other hand, defective muscles could affect other physiological functions and reduce overall immunity. “The present study clearly shows that keeping the muscle well-toned may help us keeping infections away. This is the key take away message,” signs off Dr. Nongthomba.

About the author:

Dr. Upendra Nongthomba is an Associate Professor at the Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore.

About the study:

The paper is published in the ‘Disease Models and Mechanisms’ journal (2016).