Tcf12 is required to sustain myogenic genes synergism with MyoD by remodelling the chromatin landscape.

Muscle stem cells (MuSCs) are essential for skeletal muscle development and regeneration, ensuring muscle integrity and normal function. The myogenic proliferation and differentiation of MuSCs are orchestrated by a cascade of transcription factors. In this study, we elucidate the specific role of transcription factor 12 (Tcf12) in muscle development and regeneration based on loss-of-function studies. Muscle-specific deletion of Tcf12 cause muscle weight loss owing to the reduction of myofiber size during development. Inducible deletion of Tcf12 specifically in adult MuSCs delayed muscle regeneration. The examination of MuSCs reveal that Tcf12 deletion resulted in cell-autonomous defects during myogenesis and Tcf12 is necessary for proper myogenic gene expression. Mechanistically, TCF12 and MYOD work together to stabilise chromatin conformation and sustain muscle cell fate commitment-related gene and chromatin architectural factor expressions. Altogether, our findings identify Tcf12 as a crucial regulator of MuSCs chromatin remodelling that regulates muscle cell determination and participates in skeletal muscle development and regeneration.

Retinoic acid and RARγ maintain satellite cell quiescence through regulation of translation initiation.

In adult skeletal muscle, satellite cells are in a quiescent state, which is essential for the future activation of muscle homeostasis and regeneration. Multiple studies have investigated satellite cell proliferation and differentiation, but the molecular mechanisms that safeguard the quiescence of satellite cells remain largely unknown. In this study, we purposely activated dormant satellite cells by using various stimuli and captured the in vivo-preserved features from quiescence to activation transitions. We found that retinoic acid signaling was required for quiescence maintenance. Mechanistically, retinoic acid receptor gamma (RARγ) binds to and stimulates genes responsible for Akt dephosphorylation and subsequently inhibits overall protein translation initiation in satellite cells. Furthermore, the alleviation of retinoic acid signaling released the satellite cells from quiescence, but this restraint was lost in aged cells. Retinoic acid also preserves the quiescent state during satellite cell isolation, overcoming the cellular stress caused by the isolation process. We conclude that active retinoic acid signaling contributes to the maintenance of the quiescent state of satellite cells through regulation of the protein translation initiation process.

Disturbance of calcium homeostasis and myogenesis caused by TET2 deletion in muscle stem cells.

Skeletal muscle myogenesis is a sophisticated process controlled by genetic and epigenetic regulators. In animals, one of the key enzymes for the DNA demethylation of 5-methylcytosine is TET2. Although TET2 is essential for muscle development, the mechanisms by which TET2 regulates myogenesis, particularly the implication for muscle stem cells, remains unclear. In the present study, we employed the TET2 knockout mouse model to investigate the function of TET2 in muscle development and regeneration. We observed that TET2 deficiency caused impaired muscle stem cell proliferation and differentiation, resulting in the reduction in both myofiber number and muscle tissue size. Specifically, TET2 maintains calcium homeostasis in muscle stem cells by controlling the DNA methylation levels of the calcium pathway genes. Forced expression of the sodium/calcium exchanger protein SLC8A3 could rescue the myogenic defects in TET2 knockout cells. Our data not only illustrated the vital function of TET2 during myogenesis but also identified novel targets that contribute to calcium homeostasis for enhancing muscle function.

Altered metabolic state impedes limb regeneration in salamanders.

Salamanders are unique among tetrapods in their ability to regenerate their limbs throughout life. Like other poikilothermic amphibians, salamanders also show a remarkable capacity to survive long periods of starvation. Whether the physiological reserves necessary for tissue regeneration are preserved or sacrificed in starved salamanders is unknown. In the current study, we maintained Iberian ribbed newts ( Pleurodeles waltl) under extreme physiological stress to assess the extent of regeneration and identify the molecular and cellular changes that may occur under such conditions. After 19 months of complete food deprivation, the animals exhibited extensive morphological and physiological adaptations but remained behaviorally active and vigilant. Autophagy was elevated in different tissues and the transformed gut microbiota indicated remodeling of the intestinal tract related to autophagy. Upon limb amputation in animals starved for 21 months, regeneration proceeded with progenitor cell proliferation and migration, leading to limb blastema formation. However, limb outgrowth and patterning were substantially attenuated. Blockage of autophagy inhibited cell proliferation and blastema formation in starved animals, but not in fed animals. Hence, tissue autophagy and the regenerative response were tightly coupled only when animals were under stress. Our results demonstrate that under adverse conditions, salamanders can exploit alternative strategies to secure blastema formation for limb regeneration.

miR-208b modulating skeletal muscle development and energy homoeostasis through targeting distinct targets.

Embryonic and neonatal skeletal muscles grow via the proliferation and fusion of myogenic cells, whereas adult skeletal muscle adapts largely by remodelling pre-existing myofibers and optimizing metabolic balance. It has been reported that miRNAs played key roles during skeletal muscle development through targeting different genes at post-transcriptional level. In this study, we show that a single miRNA (miR-208b) can modulate both the myogenesis and homoeostasis of skeletal muscle by distinct targets. As results, miR-208b accelerates the proliferation and inhibits the differentiation of myogenic cells by targeting the E-protein family member transcription factor 12 (TCF12). Also, miR-208b can stimulate fast-to-slow fibre conversion and oxidative metabolism programme through targeting folliculin interacting protein 1 (FNIP1) but not TCF12 gene. Further, miR-208b could active the AMPK/PGC-1a signalling and mitochondrial biogenesis through targeting FNIP1. Thus, miR-208b could mediate skeletal muscle development and homoeostasis through specifically targeting of TCF12 and FNIP1.