When bigger isn't better: understanding the anabolic resistance of obese skeletal muscle

In addition to being responsible for generating mechanical work, skeletal muscle is an important tissue for glucose disposal and overall metabolic health and, thus, should be maintained at an optimal quantity and quality across the lifespan. This is facilitated through constant remodelling of skeletal muscle via muscle protein synthesis (MPS) and muscle protein breakdown (MPB). In healthy adults, MPS and MPB are approximately equal over the course of a day, resulting in no change in net protein balance and, ultimately, lean body mass (LBM). MPS constitutes the more dynamic of the two responses and plays a role in maintaining muscle quality given its necessity to replace old and/or dysfunctional proteins. The stimulus for this process, however, can be blunted in dysfunctional tissue. A growing proportion of the population are meeting the requirements for classification as overweight or obese, characterized by excess visceral and subcutaneous adiposity. Obese individuals experience increased weight bearing load and, as a result, have increased skeletal muscle mass, but also experience poor metabolic health, such as insulin resistance. Therefore, despite a greater absolute amount of skeletal muscle, the metabolic ‘quality’ of this muscle is lesser, and probably exhibits other decrements in metabolic function. Recently, Beals and colleagues (2018) published a formative paper in The Journal of Physiology that aimed to clarify the degree to which anabolic resistance may be present in obese individuals in response to two potent anabolic stimuli: dietary protein ingestion and resistance exercise (RE). As females are consistently underrepresented in the exercise science literature, the inclusion of both sedentary, normal-weight (NW; ∼23% body fat, ∼47.8 kg LBM) and obese (OB; ∼37% body fat, ∼63.2 kg LBM) male and female participants represented a strength of the study that, despite potentially being underpowered for sex-based comparisons, arguably increases the ecological validity of the study results. The authors measured myofibrillar protein synthesis (myoPS) by primed constant infusion of l-[ring-13C6]phenylalanine in the fasted state as well as after the ingestion of 170 g of lean ground pork (4 g of fat, 36 g protein, ∼3.3 g leucine) at rest and after unilateral leg extension RE performed to volitional failure, both of which would be sufficient anabolic stimuli to maximally stimulate MPS in otherwise healthy individuals. Importantly, the use of a whole food instead of the more traditional approach of crystalline amino acids or isolated proteins is a welcome addition to the research field of muscle protein metabolism as it capitalizes on the resurgent appreciation for the anabolic potential of whole foods. The authors observed that, compared to NW, OB individuals displayed a similar increase in myoPS in response to protein feeding; however, unlike the NW group, the OB group had no further stimulation of myoPS in response to RE. As both groups had reportedly similar activity levels (as assessed by the Godin leisure-time exercise questionnaire), these findings suggest that excess adiposity per se may result in a relative ‘anabolic resistance’ to RE in OB individuals. To assess the potential underlying mechanisms involved in this aberrant muscle protein synthetic response, the authors estimated the activity (via changes in phosphorylation by traditional Western blotting) of key targets within the mammalian target of rapamycin (mTOR) pathway. Through complex interactions with downstream signalling targets, including the eukaryotic translation initiation factor 4E binding protein-1 (4E-BP1) and ribosomal protein S6 kinase (S6K), the mTOR pathway is considered the master regulator of skeletal muscle growth and, thus, MPS (Goodman et al. 2011). Interestingly, total mTOR protein content was ∼2.3-fold greater in the OB group compared to the NW group, potentially representing a compensatory upregulation of this important growth-regulating kinase in the OB population in light of their contraction-induced anabolic resistance. Despite this difference in mTOR protein expression, there was a trend towards an increased mTOR phosphorylation in NW individuals that translated into a robust increase in the phosphorylation status of S6K and 4E-BP1 following RE. In contrast, phosphorylation of these downstream signalling molecules was attenuated in OB individuals. Collectively, this suggests that the greater anabolic sensitivity of NW was related in part to a greater initiation of mRNA translation than in OB. While traditional Western blotting may infer the kinase/phosphatase activity of a myriad of intracellular targets, the molecular basis for any aberrant responses may be difficult to elucidate. It has become increasingly apparent that mTOR complex 1 (mTORC1) activity requires dynamic intracellular translocation processes in order to enhance mRNA translation. For example, the activation of mTORC1 requires its localization to the lysosome, where it interacts with active GTP-bound Rheb, which facilitates mTORC1's activation. This lysosomal targeting of mTORC1 may be a critical regulatory step in maximizing the post-exercise increase in myofibrillar protein synthesis with feeding in healthy human skeletal muscle (Abou Sawan et al. 2018). Furthermore, mTORC1-lysosome complexes migrate to the periphery of skeletal muscle fibres in response to feeding and exercise, where ribosomal machinery and capillaries containing nutrients are located (Hodson et al. 2017). Given the greater subsarcolemmal distribution of intramuscular triglycerides in OB compared to healthy individuals (Daemen et al. 2018), it would be intriguing to determine if intramuscular fat depots of OB may physically and/or biochemically interfere with the sarcolemmal targeting of mTORC1 and, thus, its kinase activity. Therefore, while traditional Western blot techniques such as those used by Beals and colleagues (2018) have long been used to estimate mTOR pathway activation, important mechanistic insights that can only be observed looking at cellular localization of signalling molecules may be missed. Thus, it is unclear to what extent dysregulated translocation events may have contributed to the blunted myoPS in OB muscle and this would represent a fruitful area of future study. Beals and colleagues (2018) hypothesized that this population may have an attenuated training-induced increase in muscle hypertrophy due to the blunted acute myoPS response observed. However, previous work has found that myoPS is elevated for up to 48 h in healthy young men (Damas et al. 2016). Thus, the acute (i.e. ∼5 h) post-exercise myoPS measurements performed by Beals and associates provide a limited snapshot of the complete myoPS response to RE. It has been proposed that the acute myoPS response to a single bout of RE in untrained individuals is primarily directed towards repairing skeletal muscle damage as opposed to increasing net protein content for hypertrophy, the latter of which may take ∼3 weeks to transition to in healthy young individuals (Damas et al. 2016). Therefore, although Beals and colleagues (2018) provide valuable insight into the acute response to a novel RE bout, future work investigating the habituated response to RE (i.e. after > 3 weeks of training) may remove potential confounding influences and provide a more comprehensive examination of skeletal muscle remodelling in clinical populations. The importance of maintaining skeletal muscle mass and quality throughout the lifespan is essential for overall health and well-being. With rates of obesity on the rise in an increasingly ageing population, the current study highlights that the potential consequences of excess body fat on the ability to remodel skeletal muscle in response to muscle contraction is, in and of itself, one of the most powerful stimuli to enhance muscle quality. If left unmanaged, this dysfunctional process could have deleterious effects as one ages. Therefore, the study by Beals and associates (2018) paves the way for the investigation into the mechanistic underpinnings of skeletal muscle metabolic dysregulation, and for future research to help determine how to make a ‘bigger’ muscle also a ‘better’ muscle. None declared. All authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. None. We appreciate the helpful discussions in EXS5531 at the University of Toronto and the feedback of Dr Daniel Moore during the preparation of this manuscript.

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