Molecules Leaking from Damaged Muscle Fibers can Activate Muscle Stem Cells

Declining muscle stem cell function appears likely to be the most important contributing cause of sarcopenia, the characteristic loss of muscle mass and strength with age. Studies of the stem populations that support muscle tissue have suggested that the cells are largely intact and capable, but quiescent. This may be a reaction to changes in signaling resulting from the age-damaged and inflammatory tissue environment, or it may be due to damage and dysfunction in the cells making up the stem cell niche, or both. Beyond the few efforts directed at repairing the underlying damage that causes these issues, such as accumulation of senescent cells, there is some interest in uncovering signals that will force muscle cells to get back to work. The research here is an example of this sort of initiative.

Skeletal muscle is made up of bundles of contracting muscle fibers and each muscle fiber is surrounded by satellite cells - muscle stem cells that can produce new muscle fibers. Thanks to the work of these satellite cells, muscle fibers can be regenerated even after being bruised or torn during intense exercise. Satellite cells also play essential roles in muscle growth during developmental stages and muscle hypertrophy during strength training. However, in refractory muscle diseases like muscular dystrophy and age-related muscular fragility (sarcopenia), the number and function of satellite cells decreases. It is therefore important to understand the regulatory mechanism of satellite cells in muscle regeneration therapy.

Since satellite cells are activated when muscle fibers are damaged, researchers hypothesized that muscle damage itself could trigger activation. However, this is difficult to prove in animal models of muscle injury so they constructed a cell culture model in which single muscle fibers, isolated from mouse muscle tissue, were physically damaged and destroyed. Using this injury model, they found that components leaking from the injured muscle fibers activated satellite cells, and the activated cells entered the G1 preparatory phase of cell division. Further, the activated cells returned to a dormant state when the damaged components were removed, thereby suggesting that the damaged components act as the activation switch.

The research team named the leaking components "Damaged myofiber-derived factors" (DMDFs), after the broken muscle fibers, and identified them using mass spectrometry. Most of the identified proteins were metabolic enzymes, including glycolytic enzymes such as GAPDH, and muscle deviation enzymes that are used as biomarkers for muscle disorders and diseases. GAPDH is known as a "moonlighting protein" that has other roles in addition to its original function in glycolysis, such as cell death control and immune response mediation. The researchers therefore analyzed the effects of DMDFs, including GAPDH, on satellite cell activation and confirmed that exposure resulted in their entry into the G1 phase. Furthermore, the researchers injected GAPDH into mouse skeletal muscle and observed accelerated satellite cell proliferation after subsequent drug-induced muscle damage. These results suggest that DMDFs have the ability to activate dormant satellite cells and induce rapid muscle regeneration after injury.

Link: https://www.eurekalert.org/pub_releases/2020-10/ku-dmd101220.php

Comments

GAPDH has quite a lot of functions in the body, so a treatment based on it would have a lot of side-effects.

Posted by: Antonio at October 19th, 2020 7:12 AM

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