5.1. Effects of 17β-TBOH on skeletal muscle
Skeletal muscle expresses ARs to varying degrees among species [178], [179], [180], [181] and [182]. As such, androgens induce skeletal muscle protein accretion following dimerization of ARs (Fig. 1). Skeletal muscle expresses 5α reductase and dose-dependently converts testosterone to DHT [183], however, our laboratory [19] and [20] and others [24] have recently demonstrated the 5α reduction of testosterone is not required for skeletal muscle maintenance in hypogonadal animals or humans. In addition, skeletal muscle expresses ERs within both sexes of various species [184], [185] and [186] and 17β-E2 administration has been shown to protect against loss of muscle strength in ovariectomized female rodents [187] and [188]; suggesting that aromatization might contribute to the effects of testosterone on skeletal muscle in males.
In ruminants, 17β-TBOH, alone or in combination with 17β-E2, has been shown to increase the cross-sectional area (CSA) of type I, but not type II, skeletal muscle fibers and induce a fiber switch from more glycolytic to more oxidative fibers, indicating an increase in the oxidative capacity of skeletal muscle [152] and [189]. However, the presence of 17β-E2 is not required for 17β-TBOH to augment skeletal muscle mass as demonstrated in rodent models which experience significant growth of the levator ani muscle [25], [26], [76], [77], [78], [79], [80] and [83] and other skeletal muscles [25], [26], [76], [77], [78], [79], [83], [117], [126] and [133] following 17β-TBOH administration, despite lacking the primary source of endogenous 17β-E2. However, not all rodent models experience peripheral (i.e., hindlimb) muscle growth following 17β-TBOH administration [115], [118] and [126]; although, elevated skeletal muscle DNA concentrations are present in muscles that do not increase in mass in response to 17β-TBOH treatment [117]. The inconsistent skeletal muscle response to 17β-TBOH in rodents may occur because certain peripheral rodent skeletal muscles possess a low percentage of AR positive myonuclei (i.e., extensor digitorum longus with 7% AR positive myonuclei) [181]. Conversely, human myonuclei are approximately 50% AR positive [182] and ruminants are highly sensitive to androgen-induced myotropic stimuli due to a high concentrations of ARs in bovine skeletal muscle [178] and [179] and skeletal muscle satellite cells [180]. Similarly, the androgen-sensitive levator ani muscle in rodents contains approximately 74% AR positive myonuclei [181] and thus experiences robust atrophic responses to castration [190] and hypertrophic responses to androgen administration [25], [26], [76], [77], [78], [79], [80] and [83].
The underlying mechanism(s) through which 17β-TBOH enhances skeletal muscle growth have not been completely characterized; although, it is suspected that 17β-TBOH exerts direct anabolic effects on skeletal muscle primarily via AR activation and associated nuclear translocation and transcription or via modulation of the Wnt/β-catenin pathway, similar to other androgens [26] (Fig. 1). In vitro evidence indicates that 17β-TBOH induces translocation of human ARs to the nucleus in a dose-dependent manner and induces gene transcription to at least the same extent as DHT, the most potent endogenous androgen [26]. Further, 17β-TBOH treatment of cultured bovine satellite cells upregulates AR mRNA expression [191], perhaps explaining the observations that administration of 17β-TBOH increases satellite cell activation and proliferation in various species [117], [191] and [192].
Additionally, 17β-TBOH may induce anabolic effects via mechanisms associated with alterations in endogenous growth factor concentrations [193] or the responsiveness of skeletal muscle to such growth factors [117] (Fig. 3). For example, 17β-TBOH alone or in combination with 17β-E2 upregulates insulin-like growth factor (IGF-1) mRNA in a variety of tissues, including the liver and skeletal muscle in vivo [140], [141], [160], [170], [191], [194] and [195] and satellite cells in vitro [140], via distinct androgen- and estrogen receptor mediated mechanisms [180] and [196]; although 17β-TBOH alone (without the addition of 17β-E2) does not appear to alter skeletal muscle IGF-1 mRNA [184]. Ultimately, the upregulation of IGF-1 mRNA translates into increased serum IGF-1 in 17β-TBOH treated animals [138], [140], [148], [150], [160], [165], [170], [192], [194], [197] and [198], which may stimulate satellite cells proliferation and fusion as has been shown in vitro [117]. Interestingly, 17β-TBOH administration also appears to increase the responsiveness of satellite cells to the proliferating and differentiating effects of IGF-1 and fibroblast growth factor [117]. These results are intriguing considering that the inhibition of several of the downstream targets of IGF-1 (e.g., Raf-1/MAPK kinase (MEK)1/2/ERK1/2, or phosphatidylinositol 3-kinase (PI3K)/Akt) suppresses 17β-TBOH induced satellite cell proliferation in culture [180]. Thus, it seems likely that increased growth factor expression resulting from 17β-TBOH administration is one mechanism underlying the anabolic responses to this steroid in skeletal muscle, especially considering that binding of IGF-1 to the type 1 IGF receptor is required for proliferation of satellite cells [180].
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Fig. 3.
Potential mechanisms underlying the anabolic effects of trenbolone on skeletal muscle. 17β-TBOH = trenbolone, GR = gluccocorticoid receptor, AR = androgen receptor, IGF-1 = insulin-like growth factor 1, IGF-1R = insulin-like growth factor 1 receptor.
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17β-TBOH may also preserve or increase lean mass via anti-catabolic effects associated with reductions in endogenous glucocorticoid activity [126] and [135] or with the suppression of amino acid degradation within the liver [118], [122], [134], [199] and [200] (Fig. 3). For example, 17β-TBOH administration has been shown to reduce circulating corticosterone concentrations in rodents [115], [118] and [122] and resting cortisol in cattle [150]. In vivo [122] and in vitro [201] evidence indicates that 17β-TBOH works in the adrenals to suppress adrenocorticotropic hormone (ACTH)-stimulated cortisol synthesis and to suppress cortisol release. Further, 17β-TBOH has been shown to reduce the ability of cortisol to bind to skeletal muscle glucocorticoid receptors (GRs) [121] and to down regulate skeletal muscle GR expression [108] and [121]. Thus the multiple anti-glucocorticoid actions induced by 17β-TBOH explain, in part, the 17β-TBOH-mediated increase in total body nitrogen retention [133], [151], [155], [156] and [202] and the reductions in total [80], [129] and [156] and myofibrillar protein degradation in several species [126], [135], [156], [202] and [203]; especially considering that 17β-TBOH reportedly reduces skeletal muscle protein synthesis in male rodents [80] and [133] B.G. Vernon and P.J. Buttery, The effect of trenbolone acetate with time on the various responses of protein synthesis of the rat, Br J Nutr 40 (1978), pp. 563–572. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (7)[133]. As a result of its anti-glucocorticoid actions, 17β-TBOH produces a more robust inhibition of protein degradation than does testosterone, which only slightly reduces protein degradation while increasing protein synthesis [204]. Thus, future research comparing the effectiveness of 17β-TBOH and the endogenous androgens in altering skeletal muscle degradation via the ubiquitin proteasome system or other pathways associated with muscle atrophy [205] is warranted and may further elucidate the anti-catabolic mechanism(s) underlying the potent augmentation of skeletal muscle mass associated with 17β-TBOH.
R-alpha lipoic acid will be a must with this though.