muscle regeneration Archives - Sanford Burnham Prebys

Tag: muscle regeneration

Institute News

MDA grant speeds research toward better treatments for Duchenne muscular dystrophy

AuthorJessica Moore
Date

September 8, 2016

Alessandra Dall'Agnese, Lorenzo Puri, MD, PhD, and Sonia Albini, PhD

Pier Lorenzo Puri, MD, PhD, professor in the Development, Aging, and Regeneration Program, has focused his career on finding treatments to counter the progression of Duchenne muscular dystrophy (DMD). A new grant from the Muscular Dystrophy Association, totaling nearly $300,000 for three years of support, will help his team figure out how to improve on a drug that they helped advance to clinical trials.

DMD, which affects hundreds of thousands of boys and young men worldwide, causes progressive muscle weakness that is usually first apparent as a child learns to walk. All patients eventually rely on a wheelchair by their high school years, and few live past their early 20s.

In DMD, the absence of a structural protein called dystrophin leads to the progressive loss of muscle fibers, as they cannot maintain their integrity following contraction. The damage triggers both repair—generation of new muscle cells—and formation of fibrous deposits, which make the muscle stiff. At first, regeneration keeps pace with the damage so the muscle continues to work, but as time goes on, the balance tips to favor scarring.

Whether the muscle regenerates or becomes fibrotic is determined by specialized cells that reside between muscle fibers, called fibro-adipogenic progenitors. The drugs that were first shown to work by Puri’s lab, histone deacetylase inhibitors (HDACis), encourage the pro-regenerative activity of these cells, while preventing them from forming fibrotic scars and promoting fat infiltration.

One HDACi, called givinostat, is in a small clinical trial in Europe. Of the 19 patients enrolled, almost all are responding with more regeneration and less fibrosis and fat infiltration. The trial is expected to expand worldwide.

“Recently, we’ve found that not all interstitial cells switch to promoting fibrosis at once,” Puri explained. “That means only some of them need to be targeted by the drug. Since we’ve figured out how to distinguish the good ones from the bad ones, we’re going to use the grant funds to look further at what’s going on in each subpopulation and see how the drug affects them.

“This research could lead to new ways to specifically target the interstitial cells that need to be redirected to foster muscle renewal.”

Puri’s recent interview on local TV station KUSI about muscular dystrophy and his research is online here.

Institute News

Boosting cells’ ability to recycle their parts to treat muscular dystrophy

AuthorJessica Moore
Date

August 15, 2016

Fluorescently stained skeletal muscle fibers showing striations

If a cell can’t efficiently recycle its machinery—energy generators, protein makers, and transport systems—it ends up using faulty equipment. Cell recycling, called autophagy, is necessary to keep cells functioning at full capacity. When autophagy doesn’t work well in muscle stem cells, which replace worn-out muscle cells, the ability to maintain healthy muscle tissue is compromised.

This is precisely what Pier Lorenzo Puri, MD, professor in the Development, Aging, and Regeneration Program, discovered in a study conducted in collaboration with Lucia Latella, PhD, at the Fondazione Santa Lucia in Rome.

Their work, published in Cell Death and Differentiation, showed that impaired autophagy in muscle stem cells of patients with advanced Duchenne muscular dystrophy (DMD) reduces their ability to support long-term regeneration. DMD is a childhood-onset genetic disorder, which mostly affects boys and causes progressive muscle weakness, invariably leading to loss of the ability to walk. As the heart and respiratory muscles also eventually deteriorate, DMD shortens lifespan, usually to less than 30 years.

They also demonstrate that boosting autophagy in a mouse model of DMD, at later stages when the recycling process slows down, improves muscle regeneration.

“These findings provide solid evidence that future drugs that increase rates of autophagy would help DMD patients,” said Puri. “In this study, mice were fed a low-protein diet to induce autophagy. The low-protein diet makes cells break down their own proteins to get the building blocks needed to make new muscle. But of course a low-protein diet isn’t a feasible approach in the long term, which is why we need drugs that specifically induce autophagy.

“Although there are several FDA-approved drugs to treat other conditions—such as high blood sugar and elevated cholesterol—they tend to have side effects that would rule them out for DMD patients. It may take a few years, but new drugs that activate autophagy in DMD patients could significantly improve their health.

Our next step will be to examine whether combining this approach with others, such as nitric oxide releasers or histone deacetylase inhibitors, which may also increase autophagy, would further promote muscle regeneration.”

The paper is available online here.

Institute News

Teaching stem cells to build muscle

Authorjmoore
Date

February 18, 2016

Header image

Researchers in Alessandra Sacco’s lab have found a key to enhancing repair of damaged muscle. In work published in Cell Reports, they describe why fetal muscle stem cells (MuSCs) are better at regenerating muscle compared to adult MuSCs. The research opens the door for new approaches to treat muscle diseases including muscular dystrophies, which affect approximately 50,000 people in the U.S., and muscle wasting associated with cancer and aging.

“We found that fetal MuSCs remodel their microenvironment by secreting specific proteins, and then examined whether that same microenvironment can encourage adult MuSCs to more efficiently generate new muscle. It does, which means that how adult MuSCs normally support muscle growth is not an intrinsic characteristic, but can be changed,” explained Matthew Tierney, a graduate student at SBP and first author of the study.

The proteins that fetal MuSCs secrete are part of the extracellular matrix (ECM), the meshwork of strand-like proteins and starches that make up the structure of MuSCs’ microenvironment. As fetal MuSCs mature into adult MuSCs, they take on different responsibilities and help change their microenvironment over time to support their distinct functions. Fetal MuSCs are geared toward creating new muscle, whereas adult MuSCs repair damaged muscle and self-replicate to sustain the pool of stem cells to mend future injuries.

In muscular dystrophies and muscle wasting, progressive degeneration overwhelms the regenerative capacity of adult MuSCs. The new study showing that adult MuSCs living in a microenvironment with fetal characteristics are better at regenerating muscle provides rationale for developing drugs that could trigger this transition.

“These results help explain the differences between the capacity of fetal and adult MuSCs to repair muscle. Such an understanding is urgently needed, as no treatments are yet available for muscular dystrophies and muscle-wasting disorders,” stated Alessandra Sacco, PhD, associate professor in the Development, Aging, and Regeneration Program at SBP and senior author of the study.

“Our findings fit with the growing appreciation of the importance of a cell’s structural and biochemical surroundings in influencing cellular behavior. Managing the microenvironment is an emerging approach to treat many diseases, from cancer to cardiovascular disease to neurodegeneration. We’re excited about the implications of our research for treating muscle diseases, and look forward to applying our conclusions toward development of therapies.”

The full text of the paper is available here.

Institute News

Researchers resolve longstanding issue of components needed to regenerate muscle

Authorsgammon
Date

February 9, 2016

Header image

Researchers at SBP have conclusively identified the protein complex that controls the genes needed to repair skeletal muscle. The discovery clears up deep-rooted conflicting data and will now help streamline efforts towards boosting stem cell-mediated muscle regeneration. Such strategies could treat muscle degenerative diseases such as muscular dystrophies, and those associated with aging and cancer. Continue reading “Researchers resolve longstanding issue of components needed to regenerate muscle”