Abstract
BackgroundSatellite cells are resident skeletal muscle stem cells responsible for muscle maintenance and repair. In resting muscle, satellite cells are maintained in a quiescent state. Satellite cell activation induces the myogenic commitment factor, MyoD, and cell cycle entry to facilitate transition to a population of proliferating myoblasts that eventually exit the cycle and regenerate muscle tissue. The molecular mechanism involved in the transition of a quiescent satellite cell to a transit-amplifying myoblast is poorly understood.MethodsSatellite cells isolated by FACS from uninjured skeletal muscle and 12 h post-muscle injury from wild type and Syndecan-4 null mice were probed using Affymetrix 430v2 gene chips and analyzed by Spotfiretm and Ingenuity Pathway analysis to identify gene expression changes and networks associated with satellite cell activation, respectively. Additional analyses of target genes identify miRNAs exhibiting dynamic changes in expression during satellite cell activation. The function of the miRNAs was assessed using miRIDIAN hairpin inhibitors.ResultsAn unbiased gene expression screen identified over 4,000 genes differentially expressed in satellite cells in vivo within 12 h following muscle damage and more than 50% of these decrease dramatically. RNA binding proteins and genes involved in post-transcriptional regulation were significantly over-represented whereas splicing factors were preferentially downregulated and mRNA stability genes preferentially upregulated. Furthermore, six computationally identified miRNAs demonstrated novel expression through muscle regeneration and in satellite cells. Three of the six miRNAs were found to regulate satellite cell fate.ConclusionsThe quiescent satellite cell is actively maintained in a state poised to activate in response to external signals. Satellite cell activation appears to be regulated by post-transcriptional gene regulation.
Highlights
Satellite cells are resident skeletal muscle stem cells responsible for muscle maintenance and repair
Wild type and Sdc4−/− satellite cells were isolated by fluorescence activated cell sorting (FACS) using anti-syndecan-3 antibodies as a marker for quiescent and proliferating satellite cells [38] from uninjured tibialis anterior (TA) muscle (Figure 1C) and TA muscles 12 h post-injury (Figure 1D)
We further examined the role of miRNAs in satellite cell activation using IngenuityW System’s IPA and identified PTEN signaling and Cell Cycle Regulation by BTG Family Proteins as the top canonical pathway regulated by miR-16, miR-93, miR-106b, and miR-124 in the transition of a quiescent satellite cell to a proliferating myoblasts (Figure 8)
Summary
Satellite cells are resident skeletal muscle stem cells responsible for muscle maintenance and repair. Satellite cells are maintained in a quiescent state. Satellite cell activation induces the myogenic commitment factor, MyoD, and cell cycle entry to facilitate transition to a population of proliferating myoblasts that eventually exit the cycle and regenerate muscle tissue. Skeletal muscle is terminally differentiated and requires a population of resident adult stem cells, satellite cells, for maintenance and repair [1,2,3]. The transition from a quiescent satellite cell to a proliferating, transit amplifying myoblast was thought to require extensive transcriptional induction as quiescent satellite cells have a low ratio of cytoplasmic volume to nuclear volume, few cellular organelles, tightly packed heterochromatin, and are believed to be metabolically inactive [12,13]. A growing pool of data demonstrates that cell fate determination is reliant on post-transcriptional gene regulation [16,17,18,19,20] and may provide mechanisms to maintain quiescent satellite cells in a ready state
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