Castration differentially alters basal and leucine-stimulated tissue protein synthesis in skeletal muscle and adipose tissue

Abstract

Reduced testosterone as a result of catabolic illness or aging is associated with loss of muscle and increased adiposity. We hypothesized that these changes in body composition occur because of altered rates of protein synthesis under basal and nutrient-stimulated conditions that are tissue specific. The present study investigated such mechanisms in castrated male rats (75% reduction in testosterone) with demonstrated glucose intolerance. Over 9 wk, castration impaired body weight gain, which resulted from a reduced lean body mass and preferential sparing of adipose tissue. Castration decreased gastrocnemius weight, but this atrophy was not associated with reduced basal muscle protein synthesis or differences in plasma IGF-I, insulin, or individual amino acids. However, oral leucine failed to normally stimulate muscle protein synthesis in castrated rats. In addition, castration-induced atrophy was associated with increased 3-methylhistidine excretion and in vitro-determined ubiquitin proteasome activity in skeletal muscle, changes that were associated with decreased atrogin-1 or MuRF1 mRNA expression. Castration decreased heart and kidney weight without reducing protein synthesis and did not alter either cardiac output or glomerular filtration. In contradistinction, the weight of the retroperitoneal fat depot was increased in castrated rats. This increase was associated with an elevated rate of basal protein synthesis, which was unresponsive to leucine stimulation. Castration also decreased whole body fat oxidation. Castration increased TNFα, IL-1α, IL-6, and NOS2 mRNA in fat but not muscle. In summary, the castration-induced muscle wasting results from an increased muscle protein breakdown and the inability of leucine to stimulate protein synthesis, whereas the expansion of the retroperitoneal fat depot appears mediated in part by an increased basal rate of protein synthesis-associated increased inflammatory cytokine expression.

Differential miRNA expression profiles in the longissimus dorsi muscle between intact and castrated male pigs

“…Previously, it was shown that castration of male rats increased body fat mass but reduced body lean mass (Jiao et al, 2009). Moreover, steers have lower skeletal muscle mass and higher lipid accumulation than intact bulls (Jeong et al, 2013).…”

Expression of androgen receptor target genes in skeletal muscle

“…Although we did not see any changes in Fbxo32 expression in vivo , expression of Fbxo32 was repressed by DHT in myoblasts in vitro . Other orchidectomy studies have shown upregulation of Fbxo32 expression in muscle,1351 with increased muscle protein degradation during atrophy,52 while androgen treatment increases muscle protein synthesis 53. Therefore, it is possible that androgen withdrawal-dependent atrophy occurs in part via the same myogenin-dependent ubiquitin ligase pathways activated in neurogenic atrophy, due to the loss of myogenin and Fbxo32 repression by the AR.…”

Androgen-mediated regulation of skeletal muscle protein balance

“…Likewise, ex vivo treatment of isolated extensor digitorum longus (EDL) and soleus muscle fiber bundles from elderly female mice (~700 days old) with 2 nM DHT increased rates of protein synthesis (Wendowski, Redshaw et al, 2016). Alternatively, castration did not change rates of protein synthesis in the tibialis anterior (TA) of mice or the gastrocnemius of rats following an overnight fast (Steiner et al, 2016, Jiao, Pruznak et al, 2009). Synthetic rates in the TA were also not different between castrated and sham mice 4 hr following refeeding, nor did castration affect the increase in protein synthesis following a bout of high frequency muscle contractions (Steiner et al, 2016).…”

“…Synthetic rates in the TA were also not different between castrated and sham mice 4 hr following refeeding, nor did castration affect the increase in protein synthesis following a bout of high frequency muscle contractions (Steiner et al, 2016). Conversely, castration prevented the leucine-induced stimulation of protein synthesis in the gastrocnemius of rats, suggesting mediation of the contributing pathways (Jiao et al, 2009). Several methodological issues may explain the discordant findings between animal studies including the feeding paradigm, model system employed, and muscle or animal species used.…”

“…Several methodological issues may explain the discordant findings between animal studies including the feeding paradigm, model system employed, and muscle or animal species used. For example, the metabolic status of the mice at sacrifice was not specified in the study by (White et al, 2013) whereas the others utilized overnight fasting and timed refeeding (Steiner et al, 2016, Jiao et al, 2009). Thus, future studies should consider using timed refeeding or overnight fasting to bypass this likely contributing factor.…”