Less is more: the role of mTORC1 activation in the progression of ageing‐mediated anabolic resistance

Skeletal muscle mass and function declines with ageing and, concomitant with other disease states and functional impairments, makes living life to the fullest a challenge. Anabolic resistance is central to age‐related skeletal muscle decrements, where signalling pathways in old muscle are disrupted and do not respond in the same way as young muscle to a growth stimulus (Kirby et al. 2015). Central to the anabolic response is the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1). Among its many functions, mTORC1 is the master regulator of protein synthesis. Once activated, mTORC1 upregulates ribosome biogenesis and mRNA translation, while shutting down catabolic pathways (i.e. autophagy, proteolysis). Disruption of normal signalling, either through muscle specific inhibition or constitutive activation, results in reduced muscle mass and insulin signalling, and fibre‐type shift towards a faster phenotype (Bentzinger et al. 2013; Castets et al. 2013). Interestingly, reduction of mTORC1 activation with rapamycin restores insulin signalling, improves muscle fibre morphology, and prevents the slow‐to‐fast fibre transition (Castets et al. 2013). Furthermore, basal mTORC1 activation is elevated during ageing (Markofski et al. 2015), and may be contributing to anabolic resistance through disruption of metabolic pathways (i.e. insulin signalling, autophagy, etc.). Collectively, this would suggest that there is a range of mTORC1 signalling that is required for muscle growth/maintenance, and deviation from this range can be detrimental. Reducing basal mTORC1 activation may actually improve gains in muscle mass in the elderly; however, this needs further investigation.

In a recent issue of The Journal of Physiology, Brook and colleagues (Brook et al. 2016) sought to investigate the cause of anabolic resistance in old humans. The authors utilized a 6 week resistance training programme to promote muscle hypertrophy and muscle protein synthesis (MPS) in young (∼23 years) and old (∼69 years) subjects. The authors hypothesized that aged individuals would have a blunted hypertrophic response after 6 weeks of resistance training when compared to the young, which is largely due to lower MPS over the course of the study. The authors used unilateral training in the study design, where one leg was trained and the other remained untrained and at rest to serve as an internal control. Muscle biopsies of the vastus lateralis were taken prior to training (baseline), and after 3 and 6 weeks of resistance training. It is important to note that the muscle biopsies in the trained leg were taken after a 60–90 min bout of resistance exercise ‘in order to investigate the temporal nature of acute anabolic signalling responses to progressive [resistance exercise]’. The subjects consumed weekly doses of deuterium oxide (D₂O) to quantify MPS via gas chromatography–pyrolysis–isotope ratio mass spectrometry.

As expected, both young and old subjects had an increase in their 1‐repetition max (1‐RM) over the course of the study; however, many of the physiological measurements (i.e. thigh fat free mass, vastus lateralis thickness, etc.) were significantly greater with resistance training in the young, but unchanged in the old subjects. To examine the molecular mechanisms behind the lack of change in lean mass, the investigators measured MPS and mTORC1 activation. They observed a significant increase in MPS from baseline to week 3 in the young, and no change in the old; however, neither young nor old subjects had a significant change in MPS from baseline to week 6. Additionally, the RNA:DNA ratio, an indicator of translational capacity, was higher after 3 and 6 weeks of training in the young but unchanged in the old. mTORC1 activation remained largely attenuated with resistance training, with significant increases only occurring during the baseline measurement in both young and old after a bout of resistance exercise. These data are somewhat surprising considering 1–2 h post resistance exercise is sufficient time to stimulate mTORC1 activation in young mice and humans. Interestingly, degradation proteins MuRF1 and MAFbx were elevated at baseline in the old but were reduced with training, although absolute breakdown rate was unchanged. This suggests other degradative pathways (autophagy, apoptosis) may be contributing to muscle loss with ageing, and are unaffected by resistance exercise. The major conclusions from this study were: (1) hypertrophy of the vastus lateralis is reduced during ageing, (2) muscle protein synthesis is blunted after 3 and 6 weeks of training in aged individuals, and (3) the lack of muscle growth is largely due to deficits in growth signalling and translational capacity.

The specific mechanisms of action behind age‐mediated anabolic resistance remain only partially defined. The work by Brook et al. adds to the collective effort to characterize the physiological and molecular response of old skeletal muscle to exercise. While not reported in this study, others have shown a significant difference in basal mTORC1 activation between young and old, with old individuals having elevated mTORC1 signalling at rest (Markofski et al. 2015). This may have a negative impact on the anabolic response of older individuals as mTORC1 can inhibit IRS‐1‐mediated glucose uptake and autophagy, both being required for muscle growth and maintenance. As basal (control leg) mTORC1 activity was not reported it is difficult to determine if hyperactive baseline mTORC1 contributed to anabolic resistance in this study. There seems to be a delicate balance with mTORC1 signalling where both too little (Bentzinger et al. 2013) and too much (Castets et al. 2013) leads to muscle dysfunction. It is fairly easy to understand how insufficient mTORC1 activation could lead to muscle wasting via inadequate ribosome biogenesis and translation initiation. On the contrary, it may seem counterintuitive that elevated mTORC1 activation can reduce muscle mass, or that inhibition of hyperactive mTORC1 can prevent muscle wasting. There is a symbiotic relationship between upstream inhibitors and activators of mTORC1 that, when disrupted, can have a negative impact on growth signalling and skeletal muscle homeostasis. There is a need for additional research investigating the relationship between anabolic resistance and mTORC1 activation, as there are many steps between the growth stimulus and protein synthesis.

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Competing interests

None declared.