A drug restored very old mice's ability to gain strength after increased muscle loading

A drug restored very old mice's ability to gain strength after increased muscle loading

In an August 7 preprint, researchers treated 28-month-old mice for two weeks with SW033291, a compound that blocks 15-PGDH, the enzyme that breaks down the signaling molecule PGE2. In a muscle overload model, foot flexor strength was approximately 50% greater in treated mice than in control animals. Single-nucleus analysis linked this effect to IGF1 growth signaling.

Muscle becomes less responsive to loading with age. Given the same workload, it gains less mass and strength. This is known as anabolic resistance. During loading, muscle fibers and the cells around them exchange signals that initiate repair and growth.

The authors surgically overloaded one lower-leg muscle, causing it to take over the work of neighboring muscles after the operation. For two weeks, they administered SW033291 daily to 28-month-old mice, which are considered very old. This molecule blocks 15-PGDH. The enzyme breaks down prostaglandin E2, or PGE2, a short-lived chemical signal involved in tissue repair.

In mice treated with the inhibitor, PGE2 levels in the overloaded muscle increased approximately threefold. Muscle mass and muscle fiber area also increased. The researchers measured foot flexor strength by electrically stimulating the nerve. Strength was approximately 50% greater in mice treated with SW033291 than in animals subjected to the same loading that received the vehicle instead of the inhibitor.

To investigate the mechanism, the researchers analyzed RNA from approximately 200 thousand cell nuclei isolated from muscle tissue. This type of analysis shows which genes are active in different cells. After 15-PGDH was blocked, Igf1 activity increased in the nuclei of one type of fast muscle fiber. Igf1 encodes the protein growth factor IGF1. A computational model of cell-to-cell interactions predicted that IGF1 could transmit signals among several cell types in muscle. When the researchers blocked the IGF1 receptor through which cells detect this signal, the gains in mass and strength were smaller.

In this model, loading initiates tissue remodeling, while 15-PGDH shortens the lifetime of PGE2. The inhibitor preserves this signal. The authors link the subsequent growth and stronger contractions to IGF1 signaling among different muscle cell types. They describe the 15-PGDH blocker as an “exercise enhancer.” In their experiment, it helped old muscle respond to loading with growth and increased strength.