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Avnika Ruparelia’s Fish Reveal Secrets of Muscle Diseases and Aging

The muscle biologist developed a zebrafish model for myofibrillar myopathies and is working with killifish to study muscle regeneration.

Sep 1, 2018
Sukanya Charuchandra

ABOVE: © CORWIN VON KUHWEDE

Born and raised in Kenya, Avnika Ruparelia moved to Australia with the hope of becoming a doctor. When her application to medical school was denied, she switched her focus to biomedical science. As someone who hates the sight of blood, the career diversion suited her. Ruparelia, now a research fellow at Monash University in Melbourne, revels in “the feeling of being the only person who knows that one thing,” she says. “It’s absolutely fantastic.”

Ruparelia got her start in research as an undergraduate in the lab of Monash muscle biologist Robert Bryson-Richardson. In 2009, she worked with him to map a gene that eventually was linked to myofibrillar myopathies (MFM), a group of diseases resulting in progressive muscle weakness that is characterized by protein clumping and structural failure within muscle cells. As Bryson-Richardson and Ruparelia began studying MFM, they and colleagues developed a zebrafish mutant model for one type of the disease, filamin-related MFM.1 This model allowed researchers to study not only filamin-related MFM, but also the normal function of filamin C, a protein found within skeletal muscles.

A year after developing the model, Ruparelia focused on a different form of MFM called BAG3-related MFM. Unlike other forms of the condition, this one is caused by mutations in a gene that plays no obvious role in muscles. The protein encoded by BAG3 normally helps dispose of malformed proteins. By expressing mutant and normal forms of BAG3 in zebrafish, Ruparelia and her colleagues found that the mutant form of the protein trapped and sequestered the functional form, eventually leading to muscle damage.2 Ruparelia, who finished her PhD at Monash in 2014, also found healthy BAG3 ensnared within aggregates of mutant filamin protein. BAG3, however, wasn’t working to clear the problematic proteins from the muscle cells. In fact, its presence within such clumps seemed to inhibit other cell-cleansing pathways as well.3

“It’s important to question the results you get and look for other explanations, not just the one you set out to test,” says Bryson-Richardson. Ruparelia, he adds, is thorough in questioning her results.

Their work allowed the pair to use a zebrafish model of BAG3-related MFM to run a drug screen to test potential therapies for the disease. Some of the drugs the researchers have identified helped zebrafish models with not only the pathology but also the muscle weakness associated with the disease. One of the drugs they’re testing is already FDA-approved to treat other conditions, which might mean it could move through clinical trials much more quickly than entirely new medicines.

“I’ve been impressed by Avnika because she’s had a very focused line of research in terms of the way that she’s approached problems and built up a very strong body of evidence to support that direction,” says her mentor for the past two years Gordon Lynch, a muscle biologist at the University of Melbourne.

Ruparelia is now setting up the first lab in Australia to use African killifish as a model organism. She spent the summer in geneticist Christoph Englert’s lab at the Leibniz Institute on Aging in Germany to learn how to use the model and to gather some preliminary data. The killifish’s short lifespan, Englert writes in an email to The Scientist, will help Ruparelia study the effect of aging on the regenerative capacity of muscle.

References

  1. A.A. Ruparelia et al., “Characterization and investigation of zebrafish models of filamin-related myofibrillar myopathy,” Hum Mol Genet, 21:4073–83, 2012. (Cited 20 times)
  2. A.A. Ruparelia et al., “Zebrafish models of BAG3 myofibrillar myopathy suggest a toxic gain of function leading to BAG3 insufficiency,” Acta Neuropathol, 128:821–33, 2014. (Cited 27 times)
  3. A.A. Ruparelia et al., “FLNC myofibrillar myopathy results from impaired autophagy and protein insufficiency,” Hum Mol Genet, 25:2131–42, 2016. (Cited 15 times)


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