New insights into muscle wasting
Muscle wasting is a severe and progressive loss of muscle mass around the skeleton, a debilitating condition for human health which leads to muscle weakness and disability. Current treatments seek to slow muscle wasting. However, there is as yet no real cure, in part because muscle wasting has no singular cause. “Muscle loss is the final output of a complex phenomenon where lots of different inputs contribute to the development of muscle atrophy,” explains Andrea Armani, Marie Curie postdoctoral fellow at the University of Padua in Italy. “Tackling the phenomenon as a whole is therefore quite complicated, especially because we still lack a pervasive knowledge of the molecular mechanisms activated in muscle wasting conditions,” he adds. In the Myo_LysoZOOM project, Armani sought to close this knowledge gap by expanding our knowledge of the underlying mechanisms that maintain and regulate muscle mass and health.
Investigating the mysterious lysosomal signature in muscle wasting
Armani’s research, funded by the Marie Skłodowska-Curie Actions programme, honed in on a specific relationship between muscle atrophy and the signalling of lysosomes. These are organelles in cells that until recently were thought to mostly just destroy and remove waste components. “In the last decade and a half or so, lysosomes have been rediscovered to be fundamental stations for cell signalling and growth, not merely degradative stations,” says Armani. This research has shown lysosomes act as signalling hubs. They modify intracellular cues in response to environmental factors – for example, regulating cellular anabolism and catabolism (the building and breakdown of molecules, respectively). As this balance between these two processes determines muscle mass, Armani and his colleagues wanted to investigate their exact function in muscle homeostasis. The team ran a series of experiments using a groundbreaking methodology to purify organelles from different muscle wasting conditions to elucidate their content and interactions. “We thus attempted to decode the mysterious lysosomal signature controlling muscle mass in health and disease,” he notes.
Unexpected results in lysosomal function
The most important discovery was that some cellular features that control cellular bioenergetics are enriched in lysosomes or in specific parts, explains Armani, however further details cannot be revealed until the research is published later this year. “The main result has been rediscovering, or better, resolving an old cytosolic process at the level of the lysosomal surface,” he says, referring to cytosol, a liquid found in most cells. “This has been possible only thanks to the methodological advancements that I optimised. These were key to resolving biological processes happening on the surface of these organelles that would have been lost with traditional methods.”
Continued research into muscle wasting
While the Myo_LysoZOOM project has finished, Armani will use the data and results as the starting point of a new research line, aimed at clarifying novel lysosomal signals important for muscle physiology. “I will lead this research line and I am currently working at the University of Zurich, where I am investigating lysosomal signalling aberrations at the basis of Pompe disease,” Armani remarks. He expects the results will be useful to the broader scientific community, as they represent the first atlas of lysosomal signalling events or signals in skeletal muscle. “Hopefully all these results will be the basis for the development of new therapies tackling different muscle pathologies, with a more knowledge-based and personalised approach,” Armani adds.
Keywords
Myo_LysoZOOM, lysosome, signature, muscle wasting, function, research
