Leading the Way in Life Science Technologies

GEN Exclusives

More »

GEN News Highlights

More »
July 14, 2017

Muscle-to-Fat Signaling Conveyed by Cellular Antennae

  • Click Image To Enlarge +
    The fatty degeneration of skeletal muscle has been associated with a signaling pathway that appears to involve stimulation of the primary cilia found on fibro/adipogenic progenitor (FAP) cells. During aging, consequent to injury, or as a result of disease, FAP cells are more likely to proliferate and give rise to fat cells. In this image, a primary cilium (red and green) is seen protruding from a FAP cell (blue). [Galo Garcia III/UCSF]

    Muscle renewal falters when our muscle cells are replaced by fat cells, a conversion that is especially marked after we suffer injury or simply grow older. An extreme form of the muscle-to-fat process is seen in muscle-wasting diseases such as Duchenne muscular dystrophy (DMD). Now, scientists at the University of California, San Francisco have shown that cellular antennae called primary cilia, found on fat-forming cells interspersed in muscle, play a key role in this muscle-to-fat transformation.

    The findings, revealed in experiments with mice, appeared July 13 in the journal Cell, in an article entitled “Ciliary Hedgehog Signaling Restricts Injury-Induced Adipogenesis.” This article points to a previously unsuspected connection between cilia and tissue renewal.

    Previous work has shown that when muscle is injured, fat-forming cells that live alongside muscle cells, called fibro/adipogenic progenitors (FAPs), divide and differentiate into fat cells. The new work indicates that, unlike muscle cells, these fat-forming FAPs are more likely to carry primary cilia, and that muscle injury further increased the abundance of FAPs with cilia. These observations suggested that cilia might be playing an important role in fat formation.

    To test this hypothesis, the UCSF research team used two mouse models of muscle injury—an acute injury model created by injecting damaging agents into mouse muscles and a chronic injury model with progressive loss of muscle fibers such as that seen in in DMD.

    “Genetically removing cilia from FAPs inhibited intramuscular adipogenesis, both after injury and in a mouse model of Duchenne muscular dystrophy,” wrote the authors of the Cell article. “Blocking FAP ciliation also enhanced myofiber regeneration after injury and reduced myofiber size decline in the muscular dystrophy model.”

    Essentially, when the scientists genetically blocked the ability of FAPs to form cilia, both injury models showed lower amounts of fat in muscle. What's more, the loss of cilia not only led to the loss of fat, but also aided muscle regeneration.

    "That was unexpected," said Daniel Kopinke, Ph.D., the first author of the new study. "We converted muscle in a mouse model of DMD into muscle that was more like that of a normal mouse."

    Through a series of experiments, the group discovered that genetically engineering cells without cilia had resulted in a low-level activation of the Hedgehog (Hh) pathway, which was enough to block fatty degeneration of skeletal muscle. When the researchers used other methods to amplify Hh signaling, mouse muscle again became less fatty.

    "I was sitting at the microscope and thought, 'Where's all the fat? It's gone!' " Dr. Kopinke said, recalling his eureka moment when he made the Hh connection. "I was almost dancing."

    With further investigation, the researchers found that a key protein in the Hh pathway called TIMP3 was responsible for the effect.

    “Hh signaling through FAP cilia regulated the expression of TIMP3, a secreted metalloproteinase inhibitor, that inhibited MMP14 to block adipogenesis,” the authors of the Cell article indicated. “A pharmacological mimetic of TIMP3 blocked the conversion of FAPs into adipocytes, pointing to a strategy to combat fatty degeneration of skeletal muscle.”

    This fresh molecular understanding could open up new prospects for regenerative medicine and one day enable researchers to improve muscle renewal during aging and disease. Already, the UCSF team is looking into other molecules that could mimic TIMP3. This work could lead to treatments for age- and injury-related muscle loss in humans.

    High levels of intramuscular fat have long been associated with a loss of strength and impaired mobility, as well as more falls in elderly or obese individuals and in patients with DMD. "The frailty of age is a huge biomedical problem," said Jeremy Reiter, M.D., Ph.D., a professor of biochemistry and biophysics at UCSF and senior author of the new paper. "This study helps pave the way to learn how muscles normally age, and provides a new way to possibly improve muscle repair."

    Dr. Reiter has a long-standing research interest in tiny cellular appendages called primary cilia, which look a bit like the cellular tentacles that paramecia and other single-celled critters use to move and gather food. But unlike those motile cilia, primary cilia don't move at all. Instead, they stand stiff and solitary on the surface of nearly all of our cells, including neurons, skin cells, bone cells, and certain stem cells.

    For centuries, these little attachments were largely ignored, and considered a vestigial structure with no known function. But "there has been a renaissance over the past decade in figuring out what these cilia do," Reiter said, and recent work by members of his lab and others has revealed that primary cilia act much like cellular antennae, receiving molecular cues from neighboring cells and processing environmental signals such as light, temperature, salt balance, and even gravity.

    Some of the best-studied examples of cilia function come from early stages of embryonic development, when the arms and legs are just tiny "buds" on the embryo. The limb buds receive cues from a fundamental cell-signaling pathway, known as Hh, that specify the number of digits you will have on your hands and feet, and tell the pinky to develop differently than the thumb. Defects in cilia can disrupt how cells interpret those signals, leading to extra fingers or toes.

    To understand if primary cilia have a role beyond development, and play a part in maintaining adult tissues, Dr. Kopinke, a postdoctoral fellow in the Reiter lab, set out to ask whether signaling by cilia is involved in muscles' ability to heal following injury. "Now for the first time we have a handle on the cell type that turns muscle into fat, and we have a handle on the signaling pathway that controls the conversion," Dr. Kopinke said. "Maybe one day we could use this knowledge to improve muscle function."

Related content

  • Finally! A cure for the Biotech News Blues.

  • Join 110,000 colleagues who rely on GEN Highlights for breaking news and exclusive articles shaping today’s life science tools and technologies.

  • Oops! Please type your email in the following format: [email protected] An error has occurred. Please contact Customer Service at [email protected]
  • You’re all set! Thank you for subscribing to GEN Highlights.