Duchenne muscular dystrophy: How muscle cells journey to the dark side

September 11, 2018, Sanford Burnham Prebys Medical Discovery Institute
Duchenne muscular dystrophy: How muscle cells journey to the dark side
Pier Lorenzo Puri, M.D., professor in the Development, Aging and Regeneration Program at Sanford Burnham Prebys Medical Discovery Institute (SBP); and lab director at Fondazione Santa Lucia IRCCS. Credit: Fondazione Santa Lucia IRCCS

Promoting repair of dystrophic muscles is a major goal in the treatment of muscular dystrophies but is complicated by the incomplete knowledge of the cellular and molecular events that drive muscle regeneration.

Answers could lie in better understanding muscle repair—which resembles a delicate cellular dance choreographed by special cells called fibro-adipogenic progenitors (FAPs). Researchers already know these cells have a dark side—they are also responsible for the and scarring that occurs during Duchenne muscular dystrophy (DMD).

Now, scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) have revealed that FAPs don't have just one identity—but several distinct identities that emerge during key stages of . Importantly, the FAPs that drive the symptoms of DMD have defined markers, meaning they could be targeted for drug development. The study was published in Nature Communications.

"There is increasing evidence from mouse studies that FAPs may play a critical role in muscle ," says Grace Pavlath, Ph.D., senior vice president and scientific program director of the Muscular Dystrophy Association (MDA). "This study provides further insight into the mechanisms underpinning impaired regeneration and the development of fibrosis in DMD, and suggests future avenues for therapeutic intervention."

DMD mostly affects boys and is caused by the absence of a muscle-strengthening protein called dystrophin. Over time, muscle is replaced by scar tissue and fat, a process called fibrosis that ultimately leads to muscle wasting and weakness. Most people with DMD do not survive past their mid-20s.

"While advances are being made, there is still an urgent need for effective treatments for DMD," says Pier Lorenzo Puri, M.D., senior author of the study; professor in the Development, Aging and Regeneration Program at SBP; and lab director at Fondazione Santa Lucia IRCCS. "This discovery reveals novel cell targets for selective interventions that may promote regeneration and prevent fibrosis in DMD muscles."

Adds Filippo Buccella, founder of the Duchenne Parent Project Italy, part of an international federation created by parents to accelerate the development of new therapies, "This major advancement sheds a new light on the complex process of muscle degeneration/regeneration and may indeed improve the lives of Duchenne patients and their families. This breakthrough comes years after working with skilled physicians and great scientists like Dr. Puri, and it will be invaluable for the many patients and families who as of today are involved worldwide with experimental clinical trials."

Mapping FAPs over time

Puri's team analyzed the transcriptome of single FAP cells, which shows the genes that are turned on or off, from samples of obtained from mouse models of and DMD. This work identified cellular markers unique to a subpopulation of FAPs (sub-FAPs).

The scientists then applied the transcriptome analysis to each of the identified sub-FAPs to track the relative amounts of gene expression and types of genes expressed in three settings of muscle regeneration: following acute injury; during DMD; and immediately after birth, which uses a different regeneration process from adult muscle repair.

Clear patterns emerged and revealed that the identified sub-FAPs transitioned through different functional states—correlating with key events during the muscle regeneration process. At early stages after acute injury, sub-FAPs expressing the cell surface marker Tie2 appear. They were followed by transient sub-FAPs expressing the cell surface marker Vcam1. Genome-wide transcriptome analysis indicated that Tie2-expressing FAPs promote blood vessel formation and muscle stem cell activation, while Vcam1-expressing sub-FAPs promote fibrosis.

"Importantly, this analysis revealed an association between these functional states and the inflammatory response of regenerating muscles," says Puri. "We observed that during acute injury, the inflammatory infiltrate—specifically macrophages—promptly cleared Vcam1-expressing sub-FAPs. This restricts their pro-fibrotic activity to transient collagen deposition, which favors optimal muscle stem cell division. However, in experimental conditions of macrophage depletion or in DMD muscles, in which macrophage activity is altered, an impaired clearance of Vcam1-expressing sub-FAPs resulted in chronic deposition of collagen and fibrosis—one of the most deleterious events in DMD progression."

Explore further: Healing mesenchymal cells morph and destroy muscles in models of spinal cord injury, ALS, spinal muscular atrophy

More information: Barbora Malecova et al, Dynamics of cellular states of fibro-adipogenic progenitors during myogenesis and muscular dystrophy, Nature Communications (2018). DOI: 10.1038/s41467-018-06068-6

Related Stories

Healing mesenchymal cells morph and destroy muscles in models of spinal cord injury, ALS, spinal muscular atrophy

July 26, 2018
When a muscle is acutely injured—whether through accidental strain or intentional weight lifting—special repair cells called fibro-adipogenic progenitors (FAPs) rush to the rescue. These cells coordinate the activity ...

Regenerating muscle in Duchenne muscular dystrophy: Age matters

April 14, 2014
A team of scientists led by Pier Lorenzo Puri, M.D., associate professor at Sanford-Burnham Medical Research Institute (Sanford-Burnham), in collaboration with Fondazione Santa Lucia in Rome, Italy, have published details ...

Researchers replicate FSH muscular dystrophy in mice

September 15, 2017
A new study published in the journal Nature Communications describes a breakthrough in research related to facioscapulohumeral muscular dystrophy (FSHD). The debilitating genetic disease - which has no approved treatment ...

Tiny cellular antennae key to fat formation in muscle

July 13, 2017
Like it or not, as we age, our muscle cells are slowly exchanged, one by one, for fat cells. This process quickens when we injure a muscle, and an extreme form of this process is also seen in muscle-wasting diseases such ...

Out-of-step cells spur muscle fibrosis in Duchenne muscular dystrophy patients

October 14, 2014
Like a marching band falling out of step, muscle cells fail to perform in unison in patients with Duchenne muscular dystrophy. A new study in The Journal of Cell Biology reveals how this breakdown leads to the proliferation ...

Recommended for you

Separated entry and exit doors for calcium keep energy production smooth in the powerhouses of heart cells

September 18, 2018
Stress demands the heart to work harder and faster. To keep pace, the muscle must make its fuel at an accelerated rate. Bursts of calcium entering mitochondria—the cell's powerhouses—normally help control energy output, ...

First gut bacteria may have lasting effect on ability to fight chronic diseases

September 18, 2018
New research showing that the first bacteria introduced into the gut have a lasting impact may one day allow science to adjust microbiomes—the one-of-a-kind microbial communities that live in our gastrointestinal tracts—to ...

A new defender for your sense of smell

September 18, 2018
New research from the Monell Center increases understanding of a mysterious sensory cell located in the olfactory epithelium, the patch of nasal tissue that contains odor-detecting olfactory receptor cells. The findings suggest ...

Small molecule plays big role in weaker bones as we age

September 18, 2018
With age, expression of a small molecule that can silence others goes way up while a key signaling molecule that helps stem cells make healthy bone goes down, scientists report.

Sperm quality study updates advice for couples trying to conceive

September 17, 2018
Could doctors at fertility clinics be giving men bad advice? Dr. Da Li and Dr. XiuXia Wang, who are clinician-researchers at the Center for Reproductive Medicine of Shengjing Hospital in Shenyang in northeast China, think ...

Antioxidant found to be effective in treating mice with osteoarthritis

September 14, 2018
A team of researchers in Belgium and the Netherlands has found that feeding a common antioxidant to test mice was effective in treating osteoarthritis. In their paper published in Science Translational Medicine, the group ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.