Scientists Accidentally Create ‘Super HGF’ That Restores Aging Muscle Repair

Deep in the packing material around every fiber of your calf muscle, a protein sits waiting. It has been waiting there for years. When you tear something, or stretch hard, or simply shove a heavy door, it’s cut loose to go and do its one job. Except that in an older muscle, quite often, it can no longer do that. A tiny chemical tag has clamped onto exactly the wrong spot, and the protein is now the wrong shape to work.

The protein is hepatocyte growth factor, or HGF, and its job is to wake people up. Not people exactly: stem cells. Every muscle fiber has a small crew of repair cells tucked against its surface, dormant for most of your life, waiting for a reason to get going. HGF is that reason. It fits into a receptor on the crew’s surface called c-met, roughly the way a key fits a lock, and the cells wake, multiply, and patch the damage. No key in the lock, no repair.

The trouble is where the tag lands. As we age, our tissues make more of a short-lived and thoroughly nasty molecule called peroxynitrite, which sticks small chemical tags onto proteins more or less at random. On HGF, two of the spots it favors are the very parts that fit into the lock. Ryuichi Tatsumi‘s group at Kyushu University showed in earlier work that this damage builds up first on fast-twitch fibers, the ones that let you sprint or catch yourself when you trip, and the ones that go first in aging humans. A grim bit of symmetry.

So the obvious reading is that old muscle runs short of repair signals. It doesn’t, not really. The signals are there. They just don’t fit anymore.

“HGF is not necessarily missing as we age,” says Tatsumi. “Rather, it can be chemically altered after it is made. That led us to wonder whether a compound with strong antioxidant capacity might protect HGF, either by preventing nitration or by compensating for the functional loss it causes.”

Three Sulfurs in a Row

The team went shopping in an odd corner of chemistry, looking for molecules that could mop up peroxynitrite before it did any damage. They settled on two compounds built around chains of three sulfur atoms. One, glutathione trisulfide, is a bulky thing based on the cell’s own workhorse antioxidant. The other, lipoic acid trisulfide, is about a third the size, and its three sulfurs are joined in a ring rather than a straight line. That ring turns out to matter enormously.

At first both behaved exactly as predicted, which is to say boringly. Mixed with HGF in a test tube and then hit with peroxynitrite, either one blocked most of the damage, and repair cells in a dish woke up more or less normally. Antioxidants doing antioxidant things. The protein’s fit into the lock came back to roughly 80 per cent of normal, decent but not exciting.

Then someone doubled the dose, and the experiment stopped behaving.

At twice the concentration, HGF treated with the ring-shaped compound gripped its receptor more than twice as tightly as HGF that had never been damaged in the first place. Not repaired. Improved. The bulkier compound, at the same dose, did nothing of the kind, and neither did ordinary lipoic acid, which is the same molecule carrying two sulfurs instead of three. “This exceeded our expectations,” Tatsumi says. “We knew trisulfides had diverse biological functions, but we never expected that simply mixing HGF with LASSS would produce such a striking effect.”

The obvious objection is that leftover compound floating around in the test tube was somehow skewing the measurement. So the team strained it out. They spun the mixture through a filter with holes fine enough to hold back the protein while letting the much smaller sulfur molecules wash straight through, three times over. The improved grip stayed behind with the protein. Whatever had happened had happened to HGF itself.

A Nudge Behind the Keyhole

What happened, exactly, nobody yet knows. The paper offers a working model built on published images of HGF locked into its receptor. Just behind the first of the two vulnerable spots, folded into the protein’s interior, sits a pair of sulfur-to-sulfur clasps that hold the local shape in place. A small ring-shaped molecule could plausibly slip in and reach those clasps where a bigger, straighter one would get stuck, trade a little sulfur chemistry, and leave the shape slightly rearranged. Slightly is enough. And there is a neat piece of supporting evidence: the protection was consistently stronger at that first spot than at the second, which sits much farther from the clasps.

“What this tells us is that LASSS does more than simply neutralize reactive molecules,” Tatsumi says. “It may interact directly with HGF and induce a subtle structural change, creating an enhanced ‘Super HGF’ form that binds c-met more strongly and resists nitration.”

Test tubes are one thing. So the group hung mice up by their tails, which sounds cruel and is in fact the standard way to take the weight off an animal’s hind legs and trigger the muscle wasting that comes from not using them. Some of the mice got the compound in their drinking water for three days beforehand, and nothing at all during the five days of suspension. Afterward the researchers sliced the calf muscles thin and used a glowing antibody that sticks only to damaged HGF. In the untreated animals the damage lit up all around the fibers. In the pretreated mice it largely didn’t. The bulky compound, so promising in the dish, failed completely.

Now the caveats. Three or four mice per group, which is small. The method used to measure the damage gives a good sense of more or less, not a precise number. The muscle loss itself hadn’t quite reached statistical significance over five days. And nobody has run the experiment that matters most, which is an old animal rather than a young immobilized one. The authors say so: there’s no direct evidence that swallowing this stuff does anything for age-related muscle loss, and the chemical change at the heart of the whole story remains unidentified.

Beyond Muscle

There is one result buried in the supplementary material that hints at something broader. The team ran the same treatment on a bland, unrelated protein from cow blood, a standard laboratory workhorse with nothing to do with muscle repair, and it too came out resistant to damage. If a small ring of sulfur can toughen up a wide range of proteins by fiddling with the clasps that hold them together, the implications spill well past muscle. The same kind of tagging shows up in Alzheimer’s, in Parkinson’s, in lung disease and heart failure.

And HGF is already a drug candidate in its own right, tested against liver scarring, spinal cord injury and ALS. A version that grips its target twice as hard and shrugs off the chemistry of diseased tissue would be worth having, assuming the improvement survives contact with a real body long enough to matter. That’s what the aging experiments will have to answer. Tatsumi’s team is talking about cats and dogs as well as people, and about livestock too, which tells you where a Faculty of Agriculture sets its horizons.

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