Sci. Aging Knowl. Environ., 20 October 2004
Vol. 2004, Issue 42, p. nf95
[DOI: 10.1126/sageke.2004.42.nf95]


Gone to Waste

Inflammation-producing compound spurs muscle deterioration

Mitch Leslie

Like a strait-laced businessman cutting loose in Las Vegas, an inflammation-controlling molecule behaves uncharacteristically in a certain milieu. New work suggests that the protein spurs muscle weakness not by prodding inflammation but by directing cells to destroy their own proteins. The work might shed light on how aging undermines strength and could lead to treatments for some types of muscle degradation that are common in the elderly.

Aging and diseases such as cancer and AIDS provoke muscle deterioration. Although researchers don't know how molecular changes sap muscle power, some work incriminates an inflammation-spurring protein called TNF-{alpha}. It rouses another protein, NF-{kappa}B, that orchestrates inflammation by activating a host of other molecules. Molecular biologist Steven Shoelson of Harvard Medical School in Boston and colleagues stumbled onto evidence implicating NF-{kappa}B in muscle wasting when they noticed that mice with an overactive version of the protein had withered muscles.

To gauge NF-{kappa}B's effects on muscle deterioration, the team engineered mice to boost or squelch NF-{kappa}B only in muscle. In one strain, known as MIKK, NF-{kappa}B activity averaged about 15 times above normal; in the other strain, known as MISC, the protein's activity plunged to about 20% of the usual value. The MIKK mice sported small muscles that generated less than one-fourth the force of normal tissue. The genetic alteration "causes muscle wasting so pronounced that it is easily visible," says Shoelson. By contrast, the MISC animals were as pumped up as control mice. MIKK rodents also excreted copious amounts of amino acids in their urine, a sign that they were rapidly dissolving proteins. Tests on isolated muscles confirmed that they were the source of the lost amino acids. The researchers stalled the disintegration by adding to the muscles a compound that clogs the proteasome, a cellular garbage disposal that minces damaged proteins. Molecules destined for destruction carry tags of the protein ubiquitin, and analysis of cells from MIKK mice suggested one reason for the apparent increased breakdown: Activity of the gene for MuRF1, which helps slap on ubiquitin tags, rose. Furthermore, NF-{kappa}B controlled MuRF1's quantities. To the team's surprise, the activity of inflammation-promoting genes stimulated by NF-{kappa}B in other tissues didn't climb in muscle. The results suggest that instead of sparking inflammation as it does in other tissues, NF-{kappa}B prods muscle cells to demolish their proteins, probably by feeding them into the proteasome. The researchers didn't identify which muscle protein gets munched, but they suspect it is mainly myosin.

The work "strongly suggests that NF-{kappa}B is important in muscle atrophy," says molecular biologist Christiaan Leeuwenburgh of the University of Florida, Gainesville. Muscle physiologist Esther Dupont-Versteegden of the University of Arkansas for Medical Sciences in Little Rock says that the findings might help researchers improve treatments for muscle withering in patients who are bedridden or suffering from cancer, two common conditions among the elderly. However, both scientists agree that NF-{kappa}B's role in causing muscle weakness associated with normal aging remains uncertain. Researchers could start to tackle the question by measuring whether the MISC mice remain bulked up as they grow old, says Dupont-Versteegden. That work might reveal whether keeping NF-{kappa}B on the straight and narrow might save muscle strength.

October 20, 2004
  1. D. Cai et al., IKK{beta}/NF-{kappa}B activation causes severe muscle wasting in mice. Cell 119, 285-298 (2004). [CrossRef][Medline]
Citation: M. Leslie, Gone to Waste. Sci. Aging Knowl. Environ. 2004 (42), nf95 (2004).

Science of Aging Knowledge Environment. ISSN 1539-6150