title: Female-specific regulation of skeletal muscle mass by USP19 in young mice.
abstract: 17β-Estradiol (E₂) is thought to be responsible for sex-specific differences in skeletal muscle mass. The biological function of E₂ is exerted through its binding to estrogen receptor α (ERα). The expression of ubiquitin-specific peptidase 19 (USP19) is upregulated during muscle atrophy and by E₂-activated ERα. Here, we investigated the involvement of USP19 in sex difference in muscle mass in young mice. Knockdown of USP19 in hindlimb muscles increased the mass and fiber size in soleus muscle in females but not males. Using Usp19 promoter reporter constructs, a functional half-estrogen response element (hERE) was identified in intron 1 of Usp19. ERα bound to hERE in an E₂-dependent manner in C2C12 myoblasts and in soleus muscle in ovariectomized (OVX) female mice. Furthermore, under normal physiological conditions, ERα bound to hERE in soleus muscle only in females. In contrast, administration of E₂ resulted in increased Usp19 mRNA expression, decreased muscle mass, and recruitment of ERα to hERE in soleus muscle in males. Knockdown of ERα in hindlimb muscles decreased Usp19 mRNA expression and increased the mass of soleus muscle only in females. Knockdown of USP19 resulted in increased levels of ubiquitin conjugates in soleus muscle in females. OVX increased the levels of ubiquitin conjugates and administration of E₂ decreased OVX-induced levels of ubiquitin conjugates. These results demonstrate that in soleus muscle in young female mice under physiological conditions, E₂ upregulates USP19 expression through ERα and consequently leads to decreases in ubiquitin conjugates and muscle mass.
authors.affiliation: Division of Applied Life SciencesGraduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka 5998531, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ogawa
authors.affiliation: Division of Applied Life SciencesGraduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka 5998531, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kitakaze
authors.affiliation: Division of Applied Life SciencesGraduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka 5998531, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Harada
authors.affiliation: Division of Applied Life SciencesGraduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka 5998531, Japan yamaji@biochem.osakafu-u.ac.jp.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Yamaji
mesh_terms: D000818:Animals; D002460:Cell Line; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004790:Enzyme Induction; D004958:Estradiol / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006614:Hindlimb; D007438:Introns; D008297:Male; D008815:Mice, Inbred Strains; D024510:Muscle Development; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000254:growth & development* / Q000378:metabolism; D010052:Ovariectomy; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D011897:Random Allocation; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D020218:Response Elements; D012727:Sex Characteristics; D064570:Ubiquitin-Specific Proteases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D047628:Estrogen Receptor alpha; D009124:Muscle Proteins; D011994:Recombinant Proteins; D004958:Estradiol; D010450:Endopeptidases; C000600175:USP19 protein, mouse; D064570:Ubiquitin-Specific Proteases
keywords: estrogen receptor α; muscle hypertrophy; skeletal muscle; ubiquitin-specific peptidase 19