Scientists at the Sanford-Burnham Medical Research Institute report the development of a new method to promote tissue repair in damaged muscles. The technique also creates a sustainable pool of muscle stem cells needed to support multiple rounds of muscle repair, according to the researchers.
The team believes its study (“STAT3 signaling controls satellite cell expansion and skeletal muscle repair”), published in Nature Medicine, provides promise for a new therapeutic approach to treating the millions of people suffering from muscle diseases, including those with muscular dystrophies and muscle wasting associated with cancer and aging.
There are two important processes that need to happen to maintain skeletal-muscle health. First, when muscle is damaged by injury or degenerative disease such as muscular dystrophy, muscle stem cells (satellite cells) need to differentiate into mature muscle cells to repair injured muscles. Second, the pool of satellite cells needs to be replenished so there is a supply to repair muscle in case of future injuries. In the case of muscular dystrophy, the chronic cycles of muscle regeneration and degeneration that involve satellite-cell activation exhaust the muscle stem-cell pool to the point of no return.
“Our study found that by introducing an inhibitor of the STAT3 protein in repeated cycles, we could alternately replenish the pool of satellite cells and promote their differentiation into muscle fibers,” said Alessandra Sacco, Ph.D., assistant professor in the development, aging, and regeneration program at Sanford-Burnham. “Our results are important because the process works in mice and in human muscle cells.”
“We show that IL-6–activated Stat3 signaling regulates satellite cell behavior, promoting myogenic lineage progression through myogenic differentiation 1 (Myod1) regulation,” wrote the investigators. “Conditional ablation of Stat3 in Pax7-expressing satellite cells resulted in their increased expansion during regeneration, but compromised myogenic differentiation prevented the contribution of these cells to regenerating myofibers. In contrast, transient Stat3 inhibition promoted satellite cell expansion and enhanced tissue repair in both aged and dystrophic muscle.”
The next step will be to see how long the cycling pattern can be extended, and to test some of the STAT3 inhibitors currently in clinical trials for other indications such as cancer.
“These findings are very encouraging. Currently, there is no cure to stop or reverse any form of muscle-wasting disorders—only medication and therapy that can slow the process,” said Vittorio Sartorelli, M.D., chief of the laboratory of muscle stem cells and gene regulation and deputy scientific director at the National Institute of Arthritis and Musculoskeletal and Skin Diseases. “A treatment approach consisting of cyclic bursts of STAT3 inhibitors could potentially restore muscle mass and function in patients, and this would be a very significant breakthrough.”