Tags

Type your tag names separated by a space and hit enter

Low Six4 and Six5 gene dosage improves dystrophic phenotype and prolongs life span of mdx mice.
Dev Growth Differ. 2016 Aug; 58(6):546-61.DG

Abstract

Muscle regeneration is an important process for skeletal muscle growth and recovery. Repair of muscle damage is exquisitely programmed by cellular mechanisms inherent in myogenic stem cells, also known as muscle satellite cells. We demonstrated previously the involvement of homeobox transcription factors, SIX1, SIX4 and SIX5, in the coordinated proliferation and differentiation of isolated satellite cells in vitro. However, their roles in adult muscle regeneration in vivo remain elusive. To investigate SIX4 and SIX5 functions during muscle regeneration, we introduced knockout alleles of Six4 and Six5 into an animal model of Duchenne Muscular Dystrophy (DMD), mdx (Dmd(mdx) /Y) mice, characterized by frequent degeneration-regeneration cycles in muscles. A lower number of small myofibers, higher number of thick ones and lower serum creatine kinase and lactate dehydrogenase activities were noted in 50-week-old Six4(+/-) 5(+/-) Dmd(mdx) /Y mice than Dmd(mdx) /Y mice, indicating improvement of dystrophic phenotypes of Dmd(mdx) /Y mice. Higher proportions of cells positive for MYOD1 and MYOG (markers of regenerating myonuclei) and SIX1 (a marker of regenerating myoblasts and newly regenerated myofibers) in 12-week-old Six4(+/-) 5(+/-) Dmd(mdx) /Y mice suggested enhanced regeneration, compared with Dmd(mdx) /Y mice. Although grip strength was comparable in Six4(+/-) 5(+/-) Dmd(mdx) /Y and Dmd(mdx) /Y mice, treadmill exercise did not induce muscle weakness in Six4(+/-) 5(+/-) Dmd(mdx) /Y mice, suggesting higher regeneration capacity. In addition, Six4(+/-) 5(+/-) Dmd(mdx) /Y mice showed 33.8% extension of life span. The results indicated that low Six4 and Six5 gene dosage improved dystrophic phenotypes of Dmd(mdx) /Y mice by enhancing muscle regeneration, and suggested that SIX4 and SIX5 are potentially useful de novo targets in therapeutic applications against muscle disorders, including DMD.

Authors+Show Affiliations

Division of Biology, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.Division of Biology, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27224259

Citation

Yajima, Hiroshi, and Kiyoshi Kawakami. "Low Six4 and Six5 Gene Dosage Improves Dystrophic Phenotype and Prolongs Life Span of Mdx Mice." Development, Growth & Differentiation, vol. 58, no. 6, 2016, pp. 546-61.
Yajima H, Kawakami K. Low Six4 and Six5 gene dosage improves dystrophic phenotype and prolongs life span of mdx mice. Dev Growth Differ. 2016;58(6):546-61.
Yajima, H., & Kawakami, K. (2016). Low Six4 and Six5 gene dosage improves dystrophic phenotype and prolongs life span of mdx mice. Development, Growth & Differentiation, 58(6), 546-61. https://doi.org/10.1111/dgd.12290
Yajima H, Kawakami K. Low Six4 and Six5 Gene Dosage Improves Dystrophic Phenotype and Prolongs Life Span of Mdx Mice. Dev Growth Differ. 2016;58(6):546-61. PubMed PMID: 27224259.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Low Six4 and Six5 gene dosage improves dystrophic phenotype and prolongs life span of mdx mice. AU - Yajima,Hiroshi, AU - Kawakami,Kiyoshi, Y1 - 2016/05/25/ PY - 2016/02/16/received PY - 2016/03/30/revised PY - 2016/04/04/accepted PY - 2016/5/26/entrez PY - 2016/5/26/pubmed PY - 2017/2/9/medline KW - Six4 KW - Six5 KW - mdx KW - muscle satellite cell KW - skeletal muscle regeneration SP - 546 EP - 61 JF - Development, growth & differentiation JO - Dev. Growth Differ. VL - 58 IS - 6 N2 - Muscle regeneration is an important process for skeletal muscle growth and recovery. Repair of muscle damage is exquisitely programmed by cellular mechanisms inherent in myogenic stem cells, also known as muscle satellite cells. We demonstrated previously the involvement of homeobox transcription factors, SIX1, SIX4 and SIX5, in the coordinated proliferation and differentiation of isolated satellite cells in vitro. However, their roles in adult muscle regeneration in vivo remain elusive. To investigate SIX4 and SIX5 functions during muscle regeneration, we introduced knockout alleles of Six4 and Six5 into an animal model of Duchenne Muscular Dystrophy (DMD), mdx (Dmd(mdx) /Y) mice, characterized by frequent degeneration-regeneration cycles in muscles. A lower number of small myofibers, higher number of thick ones and lower serum creatine kinase and lactate dehydrogenase activities were noted in 50-week-old Six4(+/-) 5(+/-) Dmd(mdx) /Y mice than Dmd(mdx) /Y mice, indicating improvement of dystrophic phenotypes of Dmd(mdx) /Y mice. Higher proportions of cells positive for MYOD1 and MYOG (markers of regenerating myonuclei) and SIX1 (a marker of regenerating myoblasts and newly regenerated myofibers) in 12-week-old Six4(+/-) 5(+/-) Dmd(mdx) /Y mice suggested enhanced regeneration, compared with Dmd(mdx) /Y mice. Although grip strength was comparable in Six4(+/-) 5(+/-) Dmd(mdx) /Y and Dmd(mdx) /Y mice, treadmill exercise did not induce muscle weakness in Six4(+/-) 5(+/-) Dmd(mdx) /Y mice, suggesting higher regeneration capacity. In addition, Six4(+/-) 5(+/-) Dmd(mdx) /Y mice showed 33.8% extension of life span. The results indicated that low Six4 and Six5 gene dosage improved dystrophic phenotypes of Dmd(mdx) /Y mice by enhancing muscle regeneration, and suggested that SIX4 and SIX5 are potentially useful de novo targets in therapeutic applications against muscle disorders, including DMD. SN - 1440-169X UR - https://www.unboundmedicine.com/medline/citation/27224259/Low_Six4_and_Six5_gene_dosage_improves_dystrophic_phenotype_and_prolongs_life_span_of_mdx_mice_ L2 - https://doi.org/10.1111/dgd.12290 DB - PRIME DP - Unbound Medicine ER -