Disruption of Gene Expression Timing in Aged Muscle Regeneration
Many of the processes taking place during tissue growth and maintenance, such as the growth of blood vessels, require correct timing in changes of behavior in the participating cells. If that timing is off, the quality of the process suffers. Disruption of complex systems is a characteristic effect of degenerative aging, and researchers here measure that outcome in the context of muscle regeneration. The shifts in gene expression that occur in different cell populations during that process become misaligned, and thus regenerative capacity suffers. Similar issues are likely taking place at a smaller scale, but more widely distributed in incidence, during the ongoing maintenance of muscle tissue, and in the response to exercise.
Skeletal muscle function and regenerative capacity decline during aging, yet factors driving these changes are incompletely understood. Muscle regeneration requires temporally coordinated transcriptional programs to drive myogenic stem cells to activate, proliferate, fuse to form myofibers, and to mature as myonuclei, restoring muscle function after injury. We assessed global changes in myogenic transcription programs distinguishing muscle regeneration in aged mice from young mice by comparing pseudotime trajectories from single-nucleus RNA sequencing of myogenic nuclei.
Aging-specific differences in coordinating myogenic transcription programs necessary for restoring muscle function occur following muscle injury, likely contributing to compromised regeneration in aged mice. Differences in pseudotime alignment of myogenic nuclei when comparing aged with young mice via dynamic time warping revealed pseudotemporal differences becoming progressively more severe as regeneration proceeds. Disruptions in timing of myogenic gene expression programs may contribute to incomplete skeletal muscle regeneration and declines in muscle function as organisms age.