Dihydrotestosterone treatment rescues the decline in protein synthesis as a result of sarcopenia in isolated mouse skeletal muscle fibres

Abstract

BackgroundSarcopenia, the progressive decline in skeletal muscle mass and function with age, is a debilitating condition. It leads to inactivity, falls, and loss of independence. Despite this, its cause(s) and the underlying mechanism(s) are still poorly understood.MethodsIn this study, small skeletal muscle fibre bundles isolated from the extensor digitorum longus (a fast‐twitch muscle) and the soleus (a slow‐twitch muscle) of adult mice of different ages (range 100–900 days old) were used to investigate the effects of ageing and dihydrotestosterone (DHT) treatment on protein synthesis as well as the expression and function of two amino acid transporters; the sodium‐coupled neutral amino acid transporter (SNAT) 2, and the sodium‐independent L‐type amino‐acid transporter (LAT) 2.ResultsAt all ages investigated, protein synthesis was always higher in the slow‐twitch than in the fast‐twitch muscle fibres and decreased with age in both fibre types. However, the decline was greater in the fast‐twitch than in the slow‐twitch fibres and was accompanied by a reduction in the expression of SNAT2 and LAT2 at the protein level. Again, the decrease in the expression of the amino acid transporters was greater in the fast‐twitch than in the slow‐twitch fibres. In contrast, ageing had no effect on SNAT2 and LAT2 expressions at the mRNA level. Treating the muscle fibre bundles with physiological concentrations (~2 nM) of DHT for 1 h completely reversed the effects of ageing on protein synthesis and the expression of SNAT2 and LAT2 protein in both fibre types.ConclusionFrom the observations that ageing is accompanied by a reduction in protein synthesis and transporter expression and that these effects are reversed by DHT treatment, we conclude that sarcopenia arises from an age‐dependent reduction in protein synthesis caused, in part, by the lack of or by the low bioavailability of the male sex steroid, DHT.

Skeletal muscle wasting in chronic heart failure

“…64 Malnutrition and sarcopenia have also been shown to be associated with early post-liver transplant morbidity/mortality, yet allocation indices do not include nutritional status. 70 In contrast to Gielen et al, 67 a strong association between high vitamin D deficiency and an increased risk of heart failure in the elderly has been described. 66 Low levels of testosterone or vitamin D were not prognostic for muscle mass and function in middle-aged and elderly men, while low insulin-like growth factor 1 (IGF-1) levels were found to predict alterations in gait speed in men aged ≥70 years.…”

Androgen-mediated regulation of skeletal muscle protein balance

“…In one study, castration decreased rates of protein synthesis in the gastrocnemius of mice, while restoration of androgens through weekly injections of nandrolone decanoate normalized this measure (White et al, 2013). 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).…”

“…Thus, future studies should consider using timed refeeding or overnight fasting to bypass this likely contributing factor. Measuring protein synthesis ex vivo could have also contributed to this discrepancy as the Ringer’s solution in which the muscles were incubated may not have mimicked the in vivo cellular environment (Wendowski et al, 2016). Differences in the muscle analyzed (gastrocnemius vs. TA) or the species of the animals (rats vs. mice) may have further contributed.…”

“…Despite these findings, the relationship between activation of either AR or PI3K and mTORC1 signaling remains elusive. Alternatively, the changes in mTORC1 signaling following androgen treatment may be due to enhanced availability of amino acids as ex vivo incubation of isolated soleus and EDL muscle fiber bundles from aged female mice with DHT increased the expression of the sodium-coupled neutral amino acid transporter (SNAT) 2 and L-type amino acid transporter (LAT) 2 channels (Wendowski et al, 2016). Collectively, these data support a role of mTORC1 in the regulation of muscle size and protein accretion by supraphysiological concentrations of androgens.…”

Preventing muscle wasting by osteoporosis drug alendronate in vitro and in myopathy models via sirtuin‐3 down‐regulation

“…19 Wendowski et al have also indicated that dihydrotestosterone could rescue an age-dependent reduction in protein synthesis of skeletal muscle fibres in sarcopenic mice. 20 A natural product, salidroside, sourced from Rhodiola rosea L., has been found to exhibit potential therapy against cancer-associated cachexia-induced limb muscle loss in tumour-borne BALB/c mice, including gastrocnemius (Gascn) muscles. 21 Moreover, anamorelin, a ghrelin-analog, could show an increase in muscle mass in cancer anorexia-cachexia syndrome.…”