Abstract
There is sexual dimorphism of skeletal muscle, the most obvious feature being the larger muscle mass of men. The molecular basis for this difference has not been clearly defined. To identify genes that might contribute to the relatively greater muscularity of men, we compared skeletal muscle gene expression profiles of 15 normal men and 15 normal women by using comprehensive oligonucleotide microarrays. Although there were sex-related differences in expression of several hundred genes, very few of the differentially expressed genes have functions that are obvious candidates for explaining the larger muscle mass of men. The men tended to have higher expression of genes encoding mitochondrial proteins, ribosomal proteins, and a few translation initiation factors. The women had >2-fold greater expression than the men (P<0.0001) of two genes that encode proteins in growth factor pathways known to be important in regulating muscle mass: growth factor receptor-bound 10 (GRB10) and activin A receptor IIB (ACVR2B). GRB10 encodes a protein that inhibits insulin-like growth factor-1 (IGF-1) signaling. ACVR2B encodes a myostatin receptor. Quantitative RT-PCR confirmed higher expression of GRB10 and ACVR2B genes in these women. In an independent microarray study of 10 men and 9 women with facioscapulohumeral dystrophy, women had higher expression of GRB10 (2.7-fold, P<0.001) and ACVR2B (1.7-fold, P<0.03). If these sex-related differences in mRNA expression lead to reduced IGF-1 activity and increased myostatin activity, they could contribute to the sex difference in muscle size.
Highlights
There is sexual dimorphism of skeletal muscle in overall mass, size of individual fibers, activities of several metabolic enzymes, lipid content and oxidation, relative expression of different myosin isoforms, fatigability, and expression of a number of genes [1,2,3,4,5,6,7,8,9]
We examined our database of expression profiles of 10 men and 9 women with facioscapulohumeral dystrophy [25] for a sex difference in expression of growth factor receptor-bound 10 (GRB10) and ACVR2B
IGF1 gene expression in muscle is sensitive to testosterone depletion or administration in men [18,29], no sex difference in plasma insulin-like growth factor-1 (IGF-1) levels or muscle IGF1 gene expression has been observed [10]
Summary
There is sexual dimorphism of skeletal muscle in overall mass, size of individual fibers, activities of several metabolic enzymes, lipid content and oxidation, relative expression of different myosin isoforms, fatigability, and expression of a number of genes [1,2,3,4,5,6,7,8,9]. The sex difference in muscle mass is presumed to be mediated by higher testosterone levels in men, because of the well known anabolic effect of testosterone [11,12,13] and because estrogens and progestins do not reduce muscle mass [14,15,16,17]. Testosterone, like all steroid hormones, exerts its effects by influencing gene expression. It has not been established which genes are responsible for its anabolic effects. While some effects of testosterone on gene expression might be limited to the period of rapid muscle growth after puberty, there must be some permanent effects to maintain the larger muscle mass in men
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