Senescent skeletal muscle myoblasts upregulate glutaminase (GLS1) through p38 MAPK signaling, generating intracellular urea that degrades mitochondrial function. Pharmacological GLS1 inhibition with CB-839 lowered urea, restored electron transport chain complex expression, and improved respiratory capacity, while progeroid mice treated with the compound gained muscle strength, endurance, and structural integrity. The work identifies glutamine metabolism as a tractable upstream driver of sarcopenia rather than a downstream consequence.
Key Points
- Senescent myoblasts overexpress glutaminase via p38 MAPK signaling
- Accumulated intracellular urea suppresses electron transport chain complexes
- CB-839 improved muscle strength and mitochondrial respiration in progeroid mice
Longevity Analysis
Muscle decline with age is frequently treated as an input problem — insufficient protein, insufficient load — when the limiting factor may be a metabolic byproduct accumulating inside the cell and suppressing energy output. Removing that interference, in this case urea generated by excess glutaminase activity, restored respiratory capacity without adding anything to the system. The same logic applies broadly: contractile tissue depends on how efficiently it produces energy and clears metabolic waste, and strength gains downstream of training may be constrained by how well those two functions are preserved.
Original published by Wiley Aging Cell, by Hamsa Vardini Senthil Kumar, Debanik Choudhury, Pedro Lei, Pihu Mehrotra, Shahryar Shahini, Sydney Swedick, John Toftegaard, Stelios T. Andreadis .