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A rapid mechanism for muscle self-repair independent of stem cells

BARCELONA (ES), October 2021 — Muscle is known to regenerate through a complex process that involves several steps and relies on stem cells. Now, a new study led by researchers at Pompeu Fabra University (UPF), Centro Nacional de Investigationes Cardiovasculares (CNIC), CIBERNED and Instituto de Medicina Molecular João Lobo Antunes describes a new mechanism for muscle repair after physiological damage relying on the rearrangement of muscle fiber nuclei, independently of muscle stem cells.

This protective mechanism paves the way to a broader understanding of muscle repair in physiology and disease.

Skeletal muscle tissue, the organ responsible for locomotion, is formed by cells (fibers) that have more than one nucleus, an almost unique feature in our body. Despite the plasticity of these fibers, their contraction can be associated with muscle damage.

William Roman, Ph.D., first author of the study (published in Science) and researcher at UPF, explained, “Even in physiological conditions, regeneration is vital for muscle to endure the mechanical stress of contraction, which often leads to cellular damage. Although muscle regeneration has been investigated in-depth in recent decades, most studies centered on mechanisms involving several cells, including muscle stem cells, which are required when extensive muscle damage occurs.”

“In this study we found an alternative mechanism of muscle tissue repair that is muscle-fiber autonomous,” said Pura Muñoz-Cánoves, Ph.D., principal investigator at UPF and the CNIC and co-leader on the study.

The researchers used different in vitro models of injury and models of exercise in mice and humans to observe that, upon injury, nuclei are attracted to the damage site, accelerating the repair of the contractile units. Next, the team dissected the molecular mechanism of this observation:

“Our experiments with muscle cells in the laboratory showed that the movement of nuclei to injury sites resulted in the local delivery of mRNA molecules. These mRNA molecules are translated into proteins at the site of injury to act as building blocks for muscle repair,” Dr. Roman explained.

“This muscle fiber self-repair process occurs rapidly both in mice and in humans after exercise-induced muscle injury, and thus represents a time- and energy-efficient protective mechanism for the repair of minor lesions,” added Dr. Muñoz-Cánoves.

In addition to its implications for muscle research, this study also introduces more general concepts for cell biology, such as the movement of nuclei to injury sites.

“One of the most fascinating things about these cells is the movement during the development of their nuclei, the biggest organelles inside the cell, but the reasons why nuclei move are largely unknown. Now, we have shown a functional relevance for this phenomenon in adulthood during cell repair and regeneration,” said Edgar R. Gomes, Ph.D., group leader at the Instituto de Medicina Molecular, who co-led the study.

On the importance of these discoveries, the researchers said that this finding “constitutes an important advance in the understanding of muscle biology, in physiology (including exercise physiology) and muscle dysfunction.”

Visualization of local damage in skeletal muscle fibers (soleous and gastro) of young mice after exercise, by staining with local damage markers such as Filamina C (green) and Evans Blue (red), and nuclei (in blue) of fibers. Image courtesy of UPF/CNIC.

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