Glutaminase inhibition improved muscle strength in a mouse model of progeria

Glutaminase inhibition improved muscle strength in a mouse model of progeria

In a study published on 7 October in Aging Cell, the authors examined senescent muscle precursor cells. They found that high activity of the enzyme GLS1 was associated with urea accumulation and impaired mitochondrial function in these cells. The drug CB-839 inhibited GLS1; after a month of treatment, mice in a model of progeria showed improvements in muscle strength, walking speed, and hanging endurance.

Mitochondria help cells produce energy. The authors induced senescence in human myoblasts, the cells that give rise to muscle fibers, using three methods: DNA damage, oxidative stress, and prolonged growth in culture. Urea levels increased within the cells in all three models.

To test the role of urea, the team suppressed SLC14A1, a protein that transports urea out of cells. In young myoblasts, this caused urea to accumulate, while oxygen consumption and respiratory chain protein levels fell. This experiment showed that excess urea can itself impair cellular respiration.

The hypothesis concerning GLS1 came from previous work from the same laboratory in another cell type, where glutamine breakdown was also linked to urea accumulation. In the current study, senescent myoblasts had increased activity of GLS1, an enzyme that initiates glutamine breakdown. The authors showed that the p38 cellular stress signaling pathway increases GLS1 activity. CB-839 reduced GLS1 activity and urea levels, alongside improvements in measures of mitochondrial respiration.

LAKI mice carrying a mutation in the LMNA gene and showing signs of accelerated aging received CB-839 three times a week for a month. GLS1 activity and urea levels decreased in their muscles, while respiratory chain protein levels, muscle fiber area, and the number of cells expressing Pax7, which participate in muscle tissue repair, increased.

The researchers then used electrical stimulation to measure muscle contraction force. Treated mice generated greater force both during a single contraction and in response to a series of rapid pulses; their muscles also relaxed faster after contraction. In movement tests, the same mice walked along a one-meter track faster and held onto an inverted grid longer. The authors thus demonstrated both cellular changes and measurable improvements in muscle function in this mouse model.