Do healthy muscles fight infections, too?

How exactly exercise helps in improving immunity against infections is still a mystery to us. 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. Can exercising help build good muscles which then in turn are better at fighting infection?

Researchers at the Indian Institute of Science (IISc), Bengaluru, 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 fruit fly (Genus: 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. The paper was published in Disease Models and Mechanisms.

Reason for choosing subjects
Why was fruit fly chosen to study innate immune reactions in muscles? “Drosophila does not have acquired immune system like higher vertebrates; so it serves as a good model to dissect the innate immune pathway,” explains Upendra Nongthomba of IISc, lead member of the 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 systems 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 makes 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. Even flies with fundamental gene mutations resulting in overall abnormal muscles (including heart muscle) showed same results.

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 emphasised the importance of maintaining optimum flight muscle (skeletal muscle) physiology for survival of flies during infection.