Fat in muscle hastens limb loss, study shows

GAINESVILLE, Fla. — For decades, treatment of peripheral artery disease has focused almost exclusively on restoring blood flow.

Now, new research from University of Florida scientists suggests that what happens inside the muscle, not just inside the artery, might determine whether patients regain their strength.

Peripheral artery disease is a vascular illness that affects over 200 million people worldwide, causing leg arteries to constrict — usually due to plaque buildup. As blood flow lessens, patients may suffer leg pain, especially when walking.

Though manageable with early diagnosis, at its worst stage, patients develop chronic limb-threatening ischemia — reduced blood flow that results in precisely what its name suggests: amputation, or limb loss.

Despite recent treatment advances, many patients continue to experience profound muscle weakness even after surgery to open their arteries and restore blood flow.

In a new study published in Circulation, researchers found that the buildup of fat inside skeletal muscle, similar to marbling in a steak, directly affects how well muscles work in patients with advanced peripheral artery disease. This fat marbling, or intramuscular adipose tissue, is more than just an incidental bystander to the vascular disease; it’s also an instigator of limb weakness.

Which, study authors point out, also makes for a potential therapeutic target.

“Right now, there’s really only a few treatments available to help these patients walk better,” said Terence Ryan, Ph.D., an associate professor in the department of applied physiology and kinesiology in the UF College of Health and Human Performance.

Current treatments center on replenishing blood flow — but are not designed to address the presence of fat inside muscle.

“Our study highlights the need to look at precisely what limits leg function and to develop new approaches,” Ryan said.

Upon analyzing calf muscle samples from patients with advanced narrowed arteries, researchers noticed that the genes responsible for creating fat cells were much active than those in individuals without the disease.

“The more fat inside the muscle tissue, the worse the muscle performed,” said Daniel Kopinke, Ph.D., an associate professor in the department of pharmacology and therapeutics in the UF College of Medicine, part of UF Health, the university’s academic health center.

Then, to determine whether the fat was a contributor to the dysfunction or a byproduct of it, researchers assessed muscle function and intramuscular fat in mice. When lots of intramuscular fat was present, the researchers found, mice had significantly weaker muscles despite having normal blood flow restored.

But when researchers altered the process by which certain proteins regulate fat production, the muscles worked better — even without changes in blood flow to the limbs.

Standard care for patients with peripheral artery disease targets arteries through surgery or by stimulating new blood vessel growth.

Instead, the study suggests that changing muscle composition plays an important role in the outcome, challenging the prevailing view that peripheral artery disease is solely a vascular problem. The buildup of fat inside muscle points to a mechanism distinct from circulation; it directly affects limb dysfunction.

Next, researchers hope to home in on what promotes fat to form in the legs of patients with limited blood flow. Improving muscle strength and walking performance remains an important goal for patients and their quality of life.

“The answer may lie not only in reopening arteries, but also in preventing muscle from turning into fat,” Kopinke said.