By David N. Leff

With Thanksgiving Day only a month away, it's almost time to talk turkey.

That thought will divide Americans into two camps: Those who speak up for white meat, such as breast, and those who elect dark meat — drumstick or giblets. The latter, in fact, are voting for flesh rich in the pigment protein myoglobin, while the former prefer helpings with the lowest possible myoglobin level.

What they're both eating, of course is muscle, skeletal muscle, which empowers turkeys and other forms of life, high and low, to fly and run. Besides this peripheral musculature, there's heart muscle, which pumps the blood that carries the hemoglobin that distributes the oxygen that fuels the body's energy output.

But what makes drumsticks dark and beefsteaks red is the iron oxide that makes up the rust-colored pigment of myoglobin. It's made only in the heart, and in the red form of skeletal muscle cells.

That protein stays out of the blood, where hemoglobin resides. Myoglobin transports oxygen from capillaries to the energy-dispensing mitochondria in heart and endurance muscle cells.

Unlike the complex, quadruple molecular network of the hemoglobins, myoglobin sports only a single heme-loaded molecule. Medical textbooks teach that stores of myoglobin supply muscles with oxygen to fuel short bursts of energy .

"We've been interested for a long time in the mechanisms by which muscle cells meet their metabolic demand," said research and clinical cardiologist R. Sanders Williams. "Particularly the hypothesis that a failure of oxygen delivery, and production of ATP, the energy molecule, is important to the pathogenesis of heart failure." Williams occupies an endowed chair in cardiovascular diseases at the University of Texas Southwestern Medical Center, in Dallas.

He is senior author of a paper in today's Nature, dated Oct. 29, 1998, succinctly titled, "Mice without myoglobin."

Myoglobin-Lacking Mice Do Very Well, Thank You

"Myoglobin expression regulation had long been a focus of our research," Williams told BioWorld Today. "We designed this study really to develop a new model of heart failure. To our surprise, we found that our knockout mice were able to live without myoglobin, and that their hearts function pretty well. The animals can exercise normally and can tolerate hypoxia [oxygen deprivation].

"The hearts of these animals," he added, "look like pale pink turkey breasts. It's actually quite dramatic, how pale they are. This confirms that myoglobin is the major pigment of the heart, and of the red skeletal muscles as well."

To explicate these counterintuitive results, Williams proposed one of two possibilities:

"Either myoglobin is not the essential protein that everyone thought it was for the past 50 or 100 years, or — the more intriguing possibility — these animals, born with no myoglobin, mount some sort of adaptive response that allows their hearts to function without that protein." He deems the latter explanation "both the more interesting and the more likely."

"We don't know what this adaptation is yet," Williams pointed out, "but I think the long-term importance of this work is if we can identify that adaptation, it might open new doors for how we would treat patients with disorders resulting from abnormal oxygen transfer — such as stroke and heart attack.

"Previous studies," he said, "had inactivated myoglobin chemically in adult animals, with catastrophic consequences. Their hearts failed immediately."

Williams and his co-authors raised a race of knockout mice lacking a functioning gene for myoglobin, and put them through their paces on an exercise treadmill — a device familiar to heart-failure patients. A cohort of myoglobin-minus animals and their normal littermates ran daily for four days on a motor-driven treadmill, which administered mild electric shocks if they lagged behind.

"The exercise capacities of myoglobin+/+ and myoglobin-/- mice were indistinguishable," the Nature paper reported.

Then the co-authors took their animals - knockouts and normals — on a virtual high-altitude climb to the top of a mountain 12,800 feet high. They simulated this breath-taking, hypoxic atmosphere by exposing the mice to a gas mixture containing 13.5 percent oxygen — well below the 18 percent to 20 percent at sea level.

"That's clearly enough," Williams said, "to make an unadapted human being breathe more quickly because of the rarified oxygen level. Not dangerous enough to cause a human to pass out, but enough to stress the cardiovascular system.

"This was meant to be a modest stress, and we would have hypothesized that the myoglobin knockout animals would have had problems, and breathe very quickly, or become unconscious. But they didn't. Their response was indistinguishable from that of normals. So again, we could detect no problem in the mice induced by the absence of myoglobin.

"The remarkable overall finding," Williams summed up, "is that these animals are pretty normal. Not only did they survive without myoglobin, they developed, reproduced, and exercised normally. That's why we thought this was a shocking result to us and the rest of the scientific community that's interested in oxygen transfer."

Wanted: Biotech Start-Up Partners

Williams added that these findings should also be of interest to the industrial drug-discovery community.

"We're very interested in biotech," he allowed. "My lab has a number of other findings that I think are quite mature, in which we are actively seeking biotech partners to advance them. This particular finding in Nature, I think, is early in the pipeline. At the point where we have identified the putative adaptations, then that becomes a potentially important target for drug development — to modify the properties of skeletal and cardiac muscle in ways that would benefit patients."

He added: "We are in active negotiations now with both major pharma companies and with venture capitalists who are interested in start-ups."

Williams noted his lab is "actually affiliated with an interesting new facility called The Center For Biomedical Invention. It's sort of like a virtual company within the university.

"We are a group of several scientists — a physicist, a chemist, a basic biologist and a physician-scientist (myself) who've banded together to add value to our basic discoveries, to make them more attractive for industry partnerships. We have over 20 patents, several of which have been licensed. And we're in active negotiations for start-ups in the Dallas area, or transfer to big pharma companies." *