Building a model of muscle loss in a cultured system, a research collaboration between Kumamoto University and Nagasaki University in Japan has found that components leaking from broken muscle fibers activate “satellite” muscle stem cells.
Attempting to identify proteins that activate satellite cells, they found that metabolic enzymes, such as GAPDH, rapidly activated inactive satellite cells and accelerated muscle injury regeneration.
It is a highly rational and efficient regeneration mechanism in which the damaged muscle itself activates satellite cells that initiate the regeneration process.
Skeletal muscle is made up of bundles of contractile 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 injury or rupture during intensive exercise.
Satellite cells play an essential role in muscle growth during the developmental stages and muscle overgrowth during strength training. However, refractory muscle diseases such as muscular dystrophy and age-related muscle fragility (sarcopenia), decrease the number and function of satellite cells. Therefore it is important to understand the regulatory mechanisms of satellite cells in muscle regeneration therapy.
In mature skeletal muscle, satellite cells are usually present in the inactive state. Upon excitation following muscle injury, satellite cells rapidly activate and spread repeatedly. During subsequent myogenesis, they detach and regenerate muscle fibers by fusing together or together with existing muscle fibers. Of these three stages (satellite cell activation, proliferation, and muscle differentiation), very few people are aware of how the first phase is activated.
Since satellite cells are activated when muscle fibers are damaged, researchers hypothesized that muscle damage may 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 injured muscle fibers from activated satellite cells, and activated cells enter the G1 early stage of cell division. In addition, activated cells return to the inactive state when damaged components are removed, suggesting that damaged components act as activation switches.
The research team named the leaked components after broken muscle fibers as “Damaged Myofiber-Derived Factors” (DMDFs), and identified them using mass spectrometry. Most of the identified proteins were metabolic enzymes, including glycolytic enzymes such as GAPDH, and muscle aberration enzymes used as biomarkers for muscle disorders and diseases.
GAPDH is known as a “moonlighting protein” that has roles other than its basic function in glycolysis, such as cell death control and immune response mediation. The researchers therefore analyzed the effects of DMDF, including GAPDH, on satellite cell activation and confirmed that the exposure was as a result of their entry into the G1 phase. In addition, researchers injected GAPDH into mouse skeletal muscle and subsequently observed accelerated satellite cell proliferation following drug-induced muscle damage.
These results suggest that DMDF has the potential to activate dormant satellite cells and induce rapid muscle regeneration after injury. The mechanism by which broken muscle activates satellite cells is a highly effective and efficient tissue regeneration mechanism.
“In this study, we proposed a new muscle injury-regeneration model. However, the detailed molecular mechanism of how DMDF activates satellite cells remains an unclear issue for future research. In addition to satellite cell activation, DMDF moonlighting functions are expected to diversify, ”said study leader Associate Professor Yusuko Ono.
“Recent studies have shown that skeletal muscle secretes a variety of factors that affect other organs and tissues, such as the brain and fat, in the bloodstream, so it may be possible that DMDFs may injure muscle in the blood circulation. And join the relationship between other organs. We believe that further expansion of the functions of DMDF can clarify the pathology of certain muscle diseases and help in the development of new drugs, ”said Ono.
(This story is published from a wire agency feed without textual modifications.)
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