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      The mechanisms of androgen effects on body composition: mesenchymal pluripotent cell as the target of androgen action.

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      Journal: The Journals of Gerontology Series A: Biological Sciences and Medical Sciences
      Keywords: Adolescent, Adult, Biopsy, Needle, Body Composition, drug effects, physiology, Child, Child, Preschool, Humans, Immunohistochemistry, Male, Muscle Development, Muscle Fibers, Skeletal, pathology, Muscle Proteins, metabolism, Muscle, Skeletal, Pluripotent Stem Cells, cytology, Sensitivity and Specificity, Stem Cells, Testosterone, administration & dosage

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          Abstract

          Testosterone supplementation increases muscle mass primarily by inducing muscle fiber hypertrophy; however, the mechanisms by which testosterone exerts its anabolic effects on the muscle are poorly understood. The prevalent view is that testosterone improves net muscle protein balance by stimulating muscle protein synthesis, decreasing muscle protein degradation, and improving the reutilization of amino acids. However, the muscle protein synthesis hypothesis does not adequately explain testosterone-induced changes in fat mass, myonuclear number, and satellite cell number. We postulate that testosterone promotes the commitment of pluripotent stem cells into the myogenic lineage and inhibits their differentiation into the adipogenic lineage. The hypothesis that the primary site of androgen action is the pluripotent stem cell provides a unifying explanation for the observed reciprocal effects of testosterone on muscle and fat mass.

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          Testosterone-induced increase in muscle size in healthy young men is associated with muscle fiber hypertrophy.

          Indrani Sinha-Hikim, Jorge N. Artaza, Linda J Woodhouse … (2002)
          Administration of replacement doses of testosterone to healthy hypogonadal men and supraphysiological doses to eugonadal men increases muscle size. To determine whether testosterone-induced increase in muscle size is due to muscle fiber hypertrophy, 61 healthy men, 18-35 yr of age, received monthly injections of a long-acting gonadotropin-releasing hormone (GnRH) agonist to suppress endogenous testosterone secretion and weekly injections of 25, 50, 125, 300, or 600 mg testosterone enanthate (TE) for 20 wk. Thigh muscle volume was measured by magnetic resonance imaging (MRI) scan, and muscle biopsies were obtained from vastus lateralis muscle in 39 men before and after 20 wk of combined treatment with GnRH agonist and testosterone. Administration of GnRH agonist plus TE resulted in mean nadir testosterone concentrations of 234, 289, 695, 1,344, and 2,435 ng/dl at the 25-, 50-, 125-, 300-, and 600-mg doses, respectively. Graded doses of testosterone administration were associated with testosterone dose and concentration-dependent increase in muscle volume measured by MRI (changes in vastus lateralis volume, -4, +7, +15, +32, and +48 ml at 25-, 50-, 125-, 300-, and 600-mg doses, respectively). Changes in cross-sectional areas of both type I and II fibers were dependent on testosterone dose and significantly correlated with total (r = 0.35, and 0.44, P < 0.0001 for type I and II fibers, respectively) and free (r = 0.34 and 0.35, P < 0.005) testosterone concentrations during treatment. The men receiving 300 and 600 mg of TE weekly experienced significant increases from baseline in areas of type I (baseline vs. 20 wk, 3,176 +/- 186 vs. 4,201 +/- 252 microm(2), P < 0.05 at 300-mg dose, and 3,347 +/- 253 vs. 4,984 +/- 374 microm(2), P = 0.006 at 600-mg dose) muscle fibers; the men in the 600-mg group also had significant increments in cross-sectional area of type II (4,060 +/- 401 vs. 5,526 +/- 544 microm(2), P = 0.03) fibers. The relative proportions of type I and type II fibers did not change significantly after treatment in any group. The myonuclear number per fiber increased significantly in men receiving the 300- and 600-mg doses of TE and was significantly correlated with testosterone concentration and muscle fiber cross-sectional area. In conclusion, the increases in muscle volume in healthy eugonadal men treated with graded doses of testosterone are associated with concentration-dependent increases in cross-sectional areas of both type I and type II muscle fibers and myonuclear number. We conclude that the testosterone induced increase in muscle volume is due to muscle fiber hypertrophy.
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            Testosterone administration to older men improves muscle function: molecular and physiological mechanisms.

            Melinda Moore, B Tipton, Arny A. Ferrando … (2002)
            We investigated the effects of 6 mo of near-physiological testosterone administration to older men on skeletal muscle function and muscle protein metabolism. Twelve older men (> or =60 yr) with serum total testosterone concentrations <17 nmol/l (480 ng/dl) were randomly assigned in double-blind manner to receive either placebo (n = 5) or testosterone enanthate (TE; n = 7) injections. Weekly intramuscular injections were given for the 1st mo to establish increased blood testosterone concentrations at 1 mo and then changed to biweekly injections until the 6-mo time point. TE doses were adjusted to maintain nadir serum testosterone concentrations between 17 and 28 nmol/l. Lean body mass (LBM), muscle volume, prostate size, and urinary flow were measured at baseline and at 6 mo. Protein expression of androgen receptor (AR) and insulin-like growth factor I, along with muscle strength and muscle protein metabolism, were measured at baseline and at 1 and 6 mo of treatment. Hematological parameters were followed monthly throughout the study. Older men receiving testosterone increased total and leg LBM, muscle volume, and leg and arm muscle strength after 6 mo. LBM accretion resulted from an increase in muscle protein net balance, due to a decrease in muscle protein breakdown. TE treatment increased expression of AR protein at 1 mo, but expression returned to pre-TE treatment levels by 6 mo. IGF-I protein expression increased at 1 mo and remained increased throughout TE administration. We conclude that physiological and near-physiological increases of testosterone in older men will increase muscle protein anabolism and muscle strength.
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              Visceral fat accumulation in men is positively associated with insulin, glucose, and C-peptide levels, but negatively with testosterone levels.

              L Sjöström, P Björntorp, R Sannerstedt … (1990)
              Twenty-three healthy men (age 25 to 50 years), covering a wide range of fatness and body fat distribution, were studied. An oral glucose tolerance test was performed and adipose tissue areas were calculated from computed tomography (CT) scans made at the level of L4/L5. Visceral fat area was associated with elevated concentrations of insulin and C-peptide and with glucose intolerance before and after the oral glucose load. Concentrations of sex-hormone-binding globulin (SHBG), as well as total and free testosterone, were negatively correlated with waist/hip circumference ratio and visceral fat area and also negatively associated with increased glucose, insulin, and C-peptide concentrations. In multiple linear regression, adjusting for age, body mass index, and visceral fat area, serum concentrations of free testosterone were still negatively correlated with glucose, insulin, and C-peptide levels. Without claiming any causality in the observed associations, we conclude that, unlike in women, abdominal fat distribution, insulin, glucose, and C-peptide levels are negatively associated with serum testosterone levels in men.
              Article 0 comments Cited 69 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                PubMed ID:: 14684707
                DOI:: 10.1093/gerona/58.12.m1103

                ScienceOpen disciplines: Chemistry
                Keywords: Adolescent,Adult,Biopsy, Needle,Body Composition,drug effects,physiology,Child,Child, Preschool,Humans,Immunohistochemistry,Male,Muscle Development,Muscle Fibers, Skeletal,pathology,Muscle Proteins,metabolism,Muscle, Skeletal,Pluripotent Stem Cells,cytology,Sensitivity and Specificity,Stem Cells,Testosterone,administration & dosage
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                ScienceOpen disciplines: Chemistry
                Keywords: Adolescent, Adult, Biopsy, Needle, Body Composition, drug effects, physiology, Child, Child, Preschool, Humans, Immunohistochemistry, Male, Muscle Development, Muscle Fibers, Skeletal, pathology, Muscle Proteins, metabolism, Muscle, Skeletal, Pluripotent Stem Cells, cytology, Sensitivity and Specificity, Stem Cells, Testosterone, administration & dosage

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