C57BL/6J-Mstn^lean/J

Stock number: 009345
Strain synonyms: C57BL/6J-Mstn<Ln>/J
Research areas: Cardiovascular Research, Diabetes and Obesity Research, Endocrine Deficiency Research, Internal/Organ Research, Metabolism Research, Neurobiology Research, Research Tools

Description

The ENU-induced lean (Ln) allele of myostatin (Mstn^Ln) leads to improper splicing and a loss-of-function allele. These Mstn^Ln mutant mice may be useful in studying diabetes, obesity, fat metabolism, protection from obesity-induced insulin resistance and other high fat diet-associated disorders, as well as Duchenne muscular dystrophy.

Detailed description

Mice homozygous for this ENU-induced mutation, called the lean (Ln) allele of myostatin (Mstn^Ln), are viable and fertile. The Mstn^Ln allele alters mRNA splicing and results in an additional larger transcript containing a 128 basepair insert at the junction between exons 2 and 3. This insertion encodes an additional 4 amino acids before a premature stop codon (ASDNX), and is predicted to generate a truncated protein containing the Mstn signal sequence and propeptide, but lacking the ligand portion of the molecule. In addition to this abnormal splicing product, the mRNA from mutant males is also reduced in abundance by approximately 60% compared to wildtype males. When maintained on normal diet, homozygous (Mstn^Ln/Ln) mice exhibit increased muscularity. When maintained on a high fat diet, homozygotes exhibit glucose tolerance, protection against overall insulin resistance, improved muscle and liver insulin sensitivity (with decreased TNFa production), and ameliorated hepatosteatosis. These Mstn^Ln mutant mice may be useful in studying diabetes, obesity, fat metabolism, and other high fat diet-associated disorders, as well as Duchenne muscular dystrophy.

Development

Following multidose N-ethyl-N-nitrosourea (ENU) treatments to induce mutations in founder C57BL/6J mice, a forward genetic screen was utilized to identify a family of mice that remained lean with low insulin despite high fat feeding. The lean phenotype was mapped to a region of chromosome 1 containing the myostatin (Mstn) gene. Sequencing of this gene identified a T->C transition in the second intron two basepairs downstream of exon 2 (a splice donor position conserved in almost all vertebrate introns). Mice harboring this ENU-induced mutation, called the lean (Ln) allele of Mstn (Mstn^Ln), were maintained on a C57BL/6J genetic background (with approximately two backcrosses to C57BL/6J) prior to arrival at The Jackson Laboratory. Upon arrival, mutant mice were bred with C57BL/6J inbred mice (Stock No. 000664) for at least one generation to establish the colony. Of note, the donating investigator reports that there may likely be other ENU-induced mutations present because these mice we not extensively backcrossed to C57BL/6J mice.

Allele

Symbol: Mstn^lean
Name: lean
MGI accession ID: MGI:3838011
Generation method: Chemically induced (ENU)
Synonyms: Mstn^Ln
Marker symbol: Mstn
Marker name: myostatin
Marker synonyms: Gdf8; MSLHP
Chromosome: 1
Strain of origin: C57BL/6J
Molecular note: Following multidose N-ethyl-N-nitrosourea (ENU) treatments to induce mutations in founder C57BL/6J mice, a T->C transition was found in the second intron two base pairs downstream of exon 2 (a splice donor position conserved in almost all vertebrate introns) in the myostatin (Mstn) gene.