Immune thrombocytopenia drug activates mitochondria, showing promise for new muscle disease therapies

Mitochondria generate energy while consuming oxygen and play an important role in muscle function. A research group led by Research Director Satoshi Inoue of the Research Team for Aging Mechanisms at the Tokyo Metropolitan Institute for Geriatrics and Gerontology, in collaboration with Saitama Medical University and the Graduate School of Medicine at the University of Tokyo, demonstrated that fostamatinib, a drug used to treat the autoimmune disease immune thrombocytopenia, may improve muscle function. The study showed that fostamatinib targets SYK (spleen tyrosine kinase), increasing mitochondrial respiratory chain supercomplexes and enhancing mitochondrial metabolism. The findings are expected to contribute to the development of new treatments and preventive strategies for muscle disorders, including sarcopenia. The results were published in the online edition of Scientific Reports.

Mitochondria are found in most cells, including muscle cells, and generate energy by consuming oxygen. In this process, protein complexes known as respiratory chain complexes within mitochondria play a major role.

The research group has previously shown that when three types of respiratory chain complexes (Complexes I, III, and IV) assemble into larger structures known as mitochondrial respiratory chain supercomplexes, they produce more energy and improve muscle function in mice. Furthermore, the group found that inhibition of SYK, a protein kinase, increases mitochondrial respiratory chain supercomplexes. As a result, SYK inhibition is expected to contribute to the development of new treatments and preventive strategies for muscle disorders, including sarcopenia.

In this study, the researchers evaluated the effects of fostamatinib, a drug that targets SYK, on mitochondrial respiratory chain supercomplexes and muscle function in aged mice, and examined its potential application to muscle disorders, including sarcopenia. Fostamatinib is metabolized in the intestine into its active metabolite, R406, which exerts the drug's effects.

The researchers first treated C2C12 cells, a mouse muscle cell model, with R406 and analyzed its effects on mitochondrial respiratory chain supercomplexes. Using visualization and spatial quantification methods for mitochondrial respiratory chain supercomplexes developed by the group, together with biochemical analyses, they found that treatment with R406 increased the abundance of mitochondrial respiratory chain supercomplexes. In addition, mitochondrial oxygen consumption increased in C2C12 cells treated with R406, indicating that mitochondrial metabolism was activated.

Next, the researchers administered fostamatinib to aged mice and evaluated muscle function using grip-strength tests and other assessments. The results showed that muscle function improved in mice treated with fostamatinib.

RNA sequencing analysis of gene expression in the quadriceps muscles of mice treated with fostamatinib revealed increased expression of gene groups involved in actin polymerization and action potentials, both of which are important for muscle function. These results suggest that fostamatinib may improve muscle function in aged mice by enhancing muscle quality.

Fostamatinib is a drug used to treat immune thrombocytopenia by targeting SYK. By analyzing fostamatinib from the perspective of mitochondrial respiratory chain supercomplexes, the researchers identified a previously unrecognized effect of the drug, namely its ability to increase mitochondrial respiratory chain supercomplexes and activate mitochondrial metabolism in muscle cells. They also demonstrated that the drug improves muscle function in aged mice. The findings are expected to support the development of new treatments and preventive strategies for sarcopenia and other muscle disorders, as well as broader applications of fostamatinib for promoting muscle health.

Department of Systems Aging Science and Medicine, Tokyo Metropolitan Institute for Geriatrics and Gerontology: https://www.tmig.or.jp/research/en/team/team01/systems-aging.html

Journal Information
Publication: Scientific Reports
Title: SYK inhibitor fostamatinib promotes mitochondrial respiratory chain supercomplex formation and improves skeletal muscle function in aged mice
DOI: 10.1038/s41598-026-65610-5