Discovery suggests new treatment for muscle atrophy

Disabled patient having rehabilitation

Researchers in Japan have revealed the key underlying mechanisms in muscle atrophy, paving the way towards potential new treatments.

While the disuse of muscles is the most frequent catalyst for muscle atrophy, there are several other possible causes, including chronic diseases, injury and exposure to low-gravity environments, such as in space travel.

Scientists from Fujita Health University have shown that mitochondria play essential roles during muscle development, regeneration and maintenance. In particular, muscle stem cells and differentiated muscle fibres (myofibres) need a lot of energy to become fully mature and functional. Thus, problems with mitochondria can immediately translate to muscle diseases, including muscle atrophy.

The team of researchers, including Junior Associate Professor Takahiko Sato, revealed the close relationship that exists between muscle atrophy, development and regeneration, and the tethering of mitochondria to the endoplasmic reticulum (ER).

Treatment with gamma-secretase inhibitors

In healthy cells, there are regions in the ER called mitochondria-associated membranes (MAMs) that can be reversibly tethered to the mitochondria. This anchoring regulates metabolism and mitochondrial morphology.

The research team conducted experiments involving ‘Mitofusin2’ (MFN2), a protein that is necessary for mitochondria tethering in MAMs.

Skeletal muscle cells cultured in a microgravity environment exhibited a sharp reduction in the number of MAMs, as well as lower levels of MFN2, alongside typical symptoms of muscle atrophy. Likewise, human cells with a mutated MFN2 gene exhibited similar traits, as well as abnormalities in mitochondrial fission and lower energy (or ATP) production, indicating problems in the generation of ‘cellular energy’.

The atrophied muscle cells all exhibited an upregulation in the Notch signalling pathway. This pathway is essential for cell communication and regulates multiple cell processes, including cell proliferation, differentiation and programmed death.

Using the gamma­secretase inhibitor DAPT, a known suppressor of Notch signalling, the researchers reverted the effects of MFN2 deficiency and partially restored mitochondrial morphology and function, as well as the number of MAMs.

The team further investigated the relationship between MAMs, MFN2, and Notch signalling in muscle atrophy in mice. The results were consistent with the in vitro experiments.

Dr Sato commented: “Our tests demonstrate that the restoration of ER-mitochondria contacts through the regulation of Notch signalling is sufficient to partially alleviate the bioenergetic defects in atrophied muscle cells. This suggests that treatment with gamma-secretase inhibitors may be a viable therapeutic option in pathological conditions in which MFN2 is involved.”

“In the future, we may be able to develop new therapeutic treatments that prevent or ameliorate muscle atrophy caused by ageing and immobility.”

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