Critical role of Frizzled1 in age‐related alterations of Wnt/β‐catenin signal in myogenic cells during differentiation

Abstract

Activation of Wnt/b-catenin signal in muscle satellite cells (mSCs) of aged mice during myogenic differentiation has been appreciated as an important age-related feature of the skeletal muscles, resulting in impairment of their regenerative ability following muscle injury. However, it remains elusive about molecules involved in this age-related alteration of Wnt/b-catenin signal in myogenic cells. To clarify this issue, we carried out expression analyses of Wnt receptor genes using real-time RT-PCR in mSCs isolated from the skeletal muscles of young and aged mice. Here, we show that expression of Frizzled1 (Fzd1) was detected at high levels in mSCs of aged mice. Higher expression levels of Fzd1 were also detected in mSC-derived myogenic cells from aged mice and associated with activation of Wnt/b-catenin signal during their myogenic differentiation in vitro. We also provide evidence that suppressed expression of Fzd1 in myogenic cells from aged mice results in a significant increase in myogenic differentiation, and its forced expression in those from young mice results in its drastic inhibition. These findings indicate the critical role of Fzd1 in altered myogenic differentiation associated with aging.

Mesenchymal stem cells of Systemic Sclerosis patients, derived from different sources, show a profibrotic microRNA profiling

“…The validated target genes, included in “TGF-beta Signalling Pathway” in Profile A are: SP1, SMAD4 and RPS6KB1, which may promote a more mature and profibrotic phenotype in MSCs 48,49 and RBL1, which may inhibit the cells proliferation by arresting the cells in G1 50 . The validated target genes, included in “Signalling Pathways Regulating Pluripotency Of Stem Cells” are: JARID2, promoting more mature phenotype in MSCs; SMAD4, pro-fibrotic 3,51 ; KAT6A and GSK3B, promoting cell proliferation 52,53 ; MEIS1 and FZD1, promoting senescence 54,55 and KRAS, promoting cell survival 56 and SMARCAD1, which may play a role during DNA repair 38 . Some down-regulated miRs, in Profile A, target specific pathways, which have not been identified in Profile BM.…”

Role of noncanonical Wnt ligands and Ror‐family receptor tyrosine kinases in the development, regeneration, and diseases of the musculoskeletal system

“…In aged mice, expression of Fzd1 is increased in SCs, resulting in suppressed myogenic differentiation of SCs, 79 indicating that canonical Wnt signaling is activated in SCs and thus inhibits myogenic differentiation of SCs in the skeletal muscles from aged mice. With this respect, it is of importance to note that the expression of Ror1 is reduced in SCs of the skeletal muscles from aged mice compared to SCs from young mice (unpublished observation).…”

The Ror1 receptor tyrosine kinase plays a critical role in regulating satellite cell proliferation during regeneration of injured muscle

“…Male C57BL/6 mice at 8 -12 weeks old were purchased from Japan SLC (Shizuoka, Japan). CTX (Latoxan, Valence, France)induced TA muscle injury experiments were performed as described previously (48). Briefly, CTX (2.5 l of 10 M CTX/g body weight) or its vehicle alone (PBS) was injected into TA muscle unilaterally.…”

“…The resultant cell suspensions were washed with ice-cold PBS containing 2% fetal bovine serum (FBS). SCs were isolated from the cell suspension by fluorescence-activated cell sorter (Moflo XDP, Beckman Coulter, Brea, CA) using anti-CD31, CD45, Sca-1, and SM/C-2.6 antibodies as described previously (35,36,48). SCs can be identified as SM/C-2.6-positive and CD31-, CD45-, and Sca-1-negative cells.…”