Drug target for muscle wasting emerges

Muscle wasting is associated with a broad range of illnesses and is also a consequence of the ageing process. It can cause generalized weakness and debilitation and in its extreme, when respiratory muscles are involved, asphyxia and even death. So it has a significant impact on patients' quality of life and their ability to cope with a disease. Now, researchers headed by a team at Joslin Diabetes Centre in the US have discovered what they believe is an important biochemical pathway for muscle wasting.

Dongsheng Cai and Steven Shoelson at Joslin - along with collaborators at Beth Israel Deaconess Medical Centre, Boston Children's Hospital, Spaulding Rehabilitation Hospital, and Regeneron Pharmaceuticals - used transgenic (genetically altered) mice to study the biochemical pathways underlying muscle wasting. Their studies zeroed in on a transcription factor called NF-(kappa)B, which is well known for its importance in immune cells but was previously not known to be a critical mediator of muscle wasting.

The investigators created two different strains of transgenic mice--MIKK mice, in which NF-(kappa)B was activated selectively in muscle tissue, and MISR mice, in which NF-(kappa)B activation was inhibited in muscle. The MIKK mice were viable and appeared normal at birth, but as they matured, their body weight was reduced due to decreases in skeletal muscle mass.

Their muscle fibres were also smaller than those of their non-genetically altered littermates. On the other hand, the MISR mice were normal in terms of appearance, body weight, and individual muscle weight and histology (the appearance of cells under the microscope) throughout life.

High doses of drugs called salicylates have been shown to inhibit NF-(kappa)B activity, so the researchers studied the impact of these drugs on MIKK mice. In one protocol, they initiated treatment with salicylates after weaning in 4-week-old MIKK mice already affected by muscle wasting. The mice's body weights increased with salicylate treatment and, after six months of therapy, their body weight, muscle mass and muscle fibre size were nearly normal.

Meanwhile, in a prevention protocol, salicylate treatment was begun during gestation. In these latter mice, body weights and muscle mass were essentially normal throughout life.

The researchers also studied the effects of blocking NF-(kappa)B activation in mouse models of muscle wasting, including immobilisation/denervation and cancer. The former is a model for the muscle wasting that occurs during disuse, such as when a limb is casted, or in spinal cord injuries. Encouragingly, inhibition of NF-(kappa)B in MISR mice was accompanied by a partial remission of denervation-induced muscle atrophy, including increased muscle mass and fibre size.

Muscle wasting is a significant problem for patients with certain forms of cancer, where it seriously diminishes their quality of life. They found that the MISR mice with cancer were protected from loosing muscle mass, and the MISR mice had much better survival rates than did normal mice with cancer.