Abstract
Muscle stem cells (MuSCs) experience age-associated declines in number and function, accompanied by mitochondrial electron transport chain (ETC) dysfunction and increased reactive oxygen species (ROS). The source of these changes, and how MuSCs respond to mitochondrial dysfunction, are unknown. We report here that in response to mitochondrial ROS, murine MuSCs directly fuse with neighboring myofibers; this phenomenon removes ETC-dysfunctional MuSCs from the stem cell compartment. MuSC–myofiber fusion is dependent on the induction of Scinderin, which promotes formation of actin-dependent protrusions required for membrane fusion. During aging, we find that the declining MuSC population accumulates mutations in the mitochondrial genome but selects against dysfunctional variants. In the absence of clearance by Scinderin, the decline in MuSC numbers during aging is repressed; however, ETC-dysfunctional MuSCs are retained and can regenerate dysfunctional myofibers. We propose a model in which ETC-dysfunctional MuSCs are removed from the stem cell compartment by fusing with differentiated tissue.
Highlights
Muscle stem cells (MuSCs) experience age-associated declines in number and function, accompanied by mitochondrial electron transport chain (ETC) dysfunction and increased reactive oxygen species (ROS)
This mechanism is cell autonomous, as ETC-dysfunctional MuSCs are able to fuse to otherwise healthy myofibers; we cannot rule out potential contributions from signaling events within the receiving myofiber or the extracellular matrix, and this constitutes a limitation of our study
This self-removal of ETC-dysfunctional stem cells by MuSC–myofiber fusion contributes to the striking decline in MuSC numbers observed during aging (Fig. 8a,b) and limits the appearance of ETC-dysfunctional MuSCs in aged animals
Summary
Muscle stem cells (MuSCs) experience age-associated declines in number and function, accompanied by mitochondrial electron transport chain (ETC) dysfunction and increased reactive oxygen species (ROS). We propose a model in which in response to elevated superoxide levels, MuSCs undergo a unique fate to be rapidly removed from muscular tissue, which is mediated by direct fusion of quiescent stem cells with preexisting myofibers. In this manner, ETC-dysfunctional MuSCs are deleted from the stem cell population and are thereby precluded from regenerating dysfunctional tissue. MuSCs retain a unique mechanism governing their response to ETC deficiency
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