Reduced expression of calcitonin receptor is closely associated with age‐related loss of the muscle stem cell pool

Abstract

Background Muscle regenerative capacity reduces during aging. Decline in the muscle stem cell (MuSC) pool is thought to be a cause of age-related muscle regeneration insufficiency. However, why the number of MuSCs decreases with age remains unclear. We previously found that the calcitonin receptor (Calcr) is expressed by MuSCs and plays a pivotal role in maintaining the MuSC pool. In this study, we examined whether Calcr is involved in the age-related decrease in MuSC number. Methods and results Calcr expression in MuSCs was assessed by immunofluorescence staining using muscle sections during postnatal growth and during aging. The role of Calcr during development, postnatal growth and adult stage was examined using mice conditionally deleted Calcr in myogenic lineage cells. To explore the significance of Calcr signaling on age-related changes in MuSC number, expression levels of endogenous Calcr ligands were examined. Immunohistological examination revealed that Calcr expression grew stronger as MuSCs became quiescent. Conditional Calcr deletion in early myogenic lineage cells did not affect the initial capacity of the MuSC pool, but promoted age-dependent MuSC loss. Expression of endogenous Calcr ligands remained unchanged with aging. Calcr expression in MuSCs, however, decreased significantly in aged muscle compared with young muscle in both mice and humans, and this reduction was accompanied by a loss of MuSCs. Conclusions Our study revealed significant reduction of Calcr in MuSCs with age, possibly leading to age-related loss of the MuSC pool. Thus, Calcr signaling could represent a promising target for preventing aging-associated muscle regeneration insufficiency.

Dlk1 regulates quiescence in calcitonin receptor-mutant muscle stem cells

“…Furthermore, loss of Dlk1 rescued the quiescent state of CalcR‐mutant MuSCs. Because decreased expression of CalcR is observed in both humans and mice during aging, 25 ectopic Dlk1 expression might contribute to the loss of MuSC pool. Further analyses of CalcR regulation and signaling pathways will improve our understanding of the mechanisms behind MuSC quiescence and age‐related loss of the MuSC pool.…”

“…Around 80% to 90% of MuSCs express CalcR protein in both humans and mice, 24,25 whereas 30% of CalcR‐cKO MuSC are positive for Dlk1. These results suggest that Dlk1 is expressed in a subset of CalcR‐cKO MuSCs.…”

“…The canonical Notch signaling also provides a surrogate ligand, collagen V, to the CalcR, which is critical for maintaining quiescence in MuSCs 22 . CalcR is specifically expressed in both human and murine quiescent MuSCs (QSCs), and CalcR expression remarkably decreased during MuSC activation or aging 23‐26 . Using MuSC‐specific conditional knockout (cKO) mice, we demonstrated that the loss of Calcr in MuSCs results in a decreased number of QSCs, an increased cell cycle‐related gene expression, and an increased number of MuSCs that escape from their niche 23 .…”

Exercise/Resistance Training and Muscle Stem Cells

“…Pax7, M-cadherin, integrin α7, and Vcam1 are widely used for the identification and purification of MuSC [16][17][18][19][20]. We identified calcitonin receptor (CalcR) as a quiescent MuSC-specific cell surface molecule in both humans and mice [21][22][23].…”

Recent developments in the field of cachexia, sarcopenia, and muscle wasting: highlights from the 12th Cachexia Conference

“…Muscle stem cell function declines during aging; therefore, the communication in the muscle stem cell niche is a target for therapeutic intervention during aging. 47 Jerome Feige (Nestlé Institute of Health Sciences, Lausanne, Switzerland) presented that muscle stem cells are responsible for skeletal muscle maintenance and healing. He impressively show that fibro-adipogenic progenitors and satellite cells crosscommunicate during muscle regeneration.…”