Muscle-Brain Crosstalk To Improve Brain Health

Dr. Mamta Rai’s interview with Bio Patrika hosting “Vigyan Patrika”, a series of author interviews. Fascinated with Mendelian Genetics taught by Mrs Neena Arora, a dedicated high school teacher, Dr. Mamta Rai took up an undergraduate course in Biomedical Sciences from University of Delhi and did her first research project during summer vacations at Dr. B R. Ambedkar Centre for Biomedical Research with Dr. Rita Singh. She worked on her master’s dissertation project, with Dr. V. M. Katoch on polymorphism typing of mycobacterium tuberculosis isolates. Her interest to pursue a career in research was largely contributed to by exposure to these research projects that she undertook to answer basic biological questions. Dr. Rai joined the laboratory of Dr. Upendra Nongthomba for PhD in Indian Institute of Science to study genes involved in Drosophila adult muscle development. She further expanded her horizons into the research of muscle biology. Following, Dr. Rai joined Dr. Fabio Demontis’ laboratory at St Jude Children’s Research Hospital (Memphis, USA) as a postdoctoral research fellow and worked on systemic benefits of skeletal muscles in brain aging. Here, Mamta talks about her work on “Proteasome stress in skeletal muscle mounts a long-range protective response that delays retinal and brain aging” published in Cell Metabolism.

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How would you explain your paper’s key results to the non-scientific community?

According to WHO, by 2050, the global population aged 60 years or older will double, emphasizing that the importance of research in healthy aging and mitigating age-related disorders is paramount. Aging is invariably related to gradual decline in brain functions leading to dementia and cognitive disabilities. Ageing brains, or brains with disorders (such as Alzheimer’s, Huntington’s, or Parkinson’s diseases) show abnormal and toxic clumps of proteins referred here as “protein aggregates”. To be able to delay brain aging and associated functional decline, prevention of accumulation of protein aggregates is imperative.

There is increasing evidence supporting the crosstalk of peripheral tissues like skeletal muscle with the brain via release of secretory factors from muscles called “myokines”. Myokines can travel in the bloodstream to target the brain and relay signals that are recognized by the brain. We found that moderate stress induced in the Drosophila skeletal muscles mediate a myokine-dependent inter-organ signaling in the brain that could mitigate age-dependent protein aggregates and hence improve brain functions.

The skeletal muscle stress was induced by suppressing the activity of proteasome (a protein degrading complex), resulting in release of myokine called Amyrel. Amyrel, by virtue of its enzymatic action, increases maltose sugar level in the blood circulation (fly hemolymph). Several sugar-sensing receptors in the brain are known to get stimulated by fluctuations in sugar levels. We found one such sugar transporter namely Slc45-2 that is responsible for the maltose signaling in the brain. Maltose signals expression of heat shock chaperones predominantly Hsp23. Chaperones are proteins that turn abnormal conformation of proteins to normal or aid degradation of protein aggregates. Hsp23 as well as other small heat shock proteins lead to clearance of protein aggregates in the brain. Additionally, we found that the maltose could also prevent heat-shock induced protein aggregates in human cortical brain organoids and restore neuronal firings post heat-shock treatment.

Overall, we identified a novel and inherent stress signaling pathway from muscles to brain via Amyrel and maltose that improves brain health during aging. Our study presents an immense potential in curbing brain diseases that are often associated with aging and dementia.

Figure 1: Schematic of the muscle-brain signaling via Amyrel and maltose in mitigation of age-induced protein aggregates in the brain.

Our study shows that it is possible to target skeletal muscle stress signaling pathways to achieve brain homeostasis.


What are the possible consequences of these findings for your research area?

Our study shows that it is possible to target skeletal muscle stress signaling pathways to achieve brain homeostasis. Activation of stress sensing pathway, without a need to induce local stress, can be utilized as potential therapeutics to treat brain diseases. We have filed a US patent for both the myokine and its disaccharide product maltose in the treatment of neurodegenerative diseases. Similarly, there are other health-benefiting signaling pathways that are most likely capable of organ crosstalk and harbor immense potential for healthy aging therapeutics.

What was the exciting moment (eureka moment) during your research?

As much joy and contentment, one gets by performing everyday bench experiments, the path to research is not a smooth ride. We wait for that one observation that either paves the path to an exciting project or brings an unexplored or a novel dimension to the ongoing research. The first eureka moment in this project was the major finding that a transient stress in the skeletal muscles could delay brain aging. The second one was finding maltose (a product of Amyrel’s enzymatic activity) as the signaling factor that increases expression of chaperones and proteases in the brain resulting in protection against age-related protein aggregate formation.

What do you hope to do next?

I am interested in pursuing research as an independent investigator in fields ranging from systemic aging, muscle atrophy, lipodystrophy to neurodegeneration.

Where do you seek scientific inspiration?

I seek my scientific inspiration from colleagues and scientist friends that I get to interact with every day. While you can find a lot of inspiration from established and well-known scientists, I believe taking lessons from scientific journeys of people you know and taking insights from their hardship, failure and success is the biggest asset of a scientific community. And last but not the least, the inquisitiveness is the biggest stimulant that drives my passion for science.

How do you intend to help Indian science improve?

Indian Science is already attracting a global audience and has proved to be at par in terms of quality and content. I would personally like to contribute to healthy aging research which I feel is a bit of an orphaned field in India. In addition, I would like to teach and share my knowledge with younger minds. Science is a fast-evolving field. To be able to pass on my skills and knowledge in theory, experimental techniques, and presentation to younger minds, I believe, will have a broad implication for representation of Indian science globally.

Reference

Mamta Rai, Zane Coleman, Michelle Curley, Anjana Nityanandam, Anna Platt, Maricela Robles-Murguia, Jianqin Jiao, David Finkelstein, Yong-Dong Wang, Beisi Xu, Yiping Fan, Fabio Demontis. Proteasome stress in skeletal muscle mounts a long-range protective response that delays retinal and brain aging. Cell Metabolism https://doi.org/10.1016/j.cmet.2021.03.005.

Dr. Fabio Demontis

Edited by: Nivedita Kamath

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