What is the relationship between acute of muscle protein synthesis response and

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1 Articles in PresS. J Appl Physiol (September 25, 2014). doi: /japplphysiol What is the relationship between acute of muscle protein synthesis response and changes in muscle mass? 3 4 Cameron J. Mitchell 1, Tyler A. Churchward-Venne 2, David Cameron-Smith 1, Stuart M. Phillips 3* Liggins Institute, University of Auckland, Auckland, New Zealand; 2 Department of Human Movement Sciences, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands; 3 Exercise Metabolism Research Group, Department of Kinesiology, McMaster University, Hamilton, Ontario, Canada *Corresponding author: Professor Stuart M. Phillips The Department of Kinesiology, McMaster University, 1280 Main Street West Hamilton Ontario L8S 4L8, Canada 16 phillis@mcmaster.ca 17 P: x24465 Copyright 2014 by the American Physiological Society.

2 Rates of synthesis of skeletal muscle protein pools (myofibrillar, mitochondrial, sarcoplasmic) are often directly measured through determination of the fractional synthetic rate (FSR) using stable isotope tracer labelled amino acids. This is accomplished by measuring the incorporation of tracer amino acid into muscle protein (bound enrichment), determining the enrichment of the precursor pool, and dividing the incorporation of amino acid tracer over a given period of time by the precursor enrichment yielding a rate in % per unit time (3, 22). Measures of muscle protein FSR, often referred to as muscle protein synthesis (MPS), have been routinely employed to examine the acute effects (i.e., several hours to 24 hours) of various exercise and nutritional stimuli. This begs the question as to whether acute early changes in MPS, particularly following resistance exercise (RE), relate to the magnitude of muscle hypertrophy in longer-term training studies? It has been proposed that chronic adaptation (i.e., muscle hypertrophy) with resistance training (RT) occur as a result of summed periods of repeated acute exercise-induced positive protein balance where MPS exceeds muscle protein breakdown (MPB) (20). In such a scenario, one thesis is that the clearly established heterogeneity of the hypertrophic response to resistance training (8, 14, 15) may be explained, to some degree, by divergent responses of MPS to acute exercise stimuli; but is this the case? It is possible the variations in MPB are also important for the regulation of muscle hypertrophy however, the measurement of MPB is hampered by methodological limitations and thus is reported infrequently. The magnitude of regulation of MBP is much smaller than MPS (7). Additional resistance exercise appears to regulate MPB and MPS in a concomitant manner (21). We believe that although it would be ideal to measure the balance between MPS and MPB that MPS is likely to have a greater relationship with hypertrophy than MPB. To date, only a single study has reported the within-subject association between acute MPS rates after RE and skeletal muscle hypertrophy following prolonged RT (15). Another

3 study attempted to correlated MPS measured 24h after the first training session with muscle hypertrophy (14) In neither study was a linear correlation between MPS and hypertrophy observed (14, 15). The lack of a correlation between pre training measures of MPS and muscle hypertrophy after prolonged training may lead one to question the value of acute measurements of MPS to yield insight into phenotypic adaptations following RT. Nonetheless, while acute MPS response is not always quantitatively related to muscle hypertrophy, there are a number of examples where MPS response following an acute intervention (nutrition and/or exercise) is aligned with changes in muscle hypertrophy in different subject cohorts. Multiple studies from our laboratory (2, 3, 8, 16, 27, 28, 31), and others (9, 10) have demonstrated that patterns of change in acute (i.e. over several hours) of MPS response following a single session RE were aligned with the adaptive hypertrophic response following repeated exposure (i.e. for several weeks) to a similar dietary/exercise intervention. For example, the acute MPS response following post-re consumption of milk versus a soy beverage (31) was qualitatively aligned with changes in lean body mass obtained following 12 weeks of RT and the same protein supplementation (8). In addition, the response of MPS following RE employing lower load contractions (3) and RE bouts employing greater volumes of work (three sets versus one set) (2), were congruent with the hypertrophic response following a period of RT employing these training protocols (16). However, the magnitude of the acute response of MPS and the subsequent hypertrophy with the same stimuli in RT is highly variable between individuals. The source of such hypertrophic variability is likely due to an individual s inherited genetic predisposition, epigenetic influence, and transcriptional plasticity, all of which are likely further impacted by factors such as age, habitual physical activity, and training status. For example, multiple set training has been demonstrated to elicit a greater acute response of MPS (2) and training mediated muscle hypertrophy (12, 16) than single set training, however a hypertrophic

4 responder to resistance exercise may demonstrate a greater response both acutely (i.e. MPS), and in response to RT (i.e. muscle hypertrophy), following single set training, than a nonresponder to multi-set RT. We propose that the response heterogeneity to RT (8, 14) is often overlooked but it is inherently hard to modify and highlights the importance of adequate sample size to detect differences in the hypertrophic response to various exercise/nutritional stimuli In comparison to younger persons older persons have a lower MPS rates in response to protein feeding and exercise (5, 13, 17), a condition termed anabolic resistance (5). Reductions in loading/physical activity very quickly lead to reductions in anabolic sensitivity to feeding (1, 6, 26). Conversely, even relatively short-duration moderate intensity aerobic exercise performed 15 hours earlier improves the MPS response to meal feeding (25). We hypothesize that physical activity in the hours, possibly days, before measurement of MPS, as well as habitual levels of physical activity and training status, can have a significant impact on magnitude of the MPS response to feeding (25) and possibly exercise. To date, only a few studies have measured MPS in both the trained and untrained state within the same individuals (11, 24, 29). These studies have shown that RT generally reduces the duration of the acute MPS response to a session of RE preformed at the same relative intensity (11, 24); however, we do not know when in a RT program this change occurs. It is known, however, that the transcriptional response following the first exercise session is reflective of muscle damage and differs substantially from a second RE bout performed 48 h later (18). In addition, integrated daily MPS rates were shown to be lower after only two workouts during an 8 day resistance training period (29). Thus, it appears that very little training is required to modify the acute transcriptional (18) and protein synthetic (11, 24, 29) responses to a bout of RE, at least of the same relative intensity. These observations (11, 18, 24, 29) suggest that acute measurement of the response of MPS to RE is not going to be useful in predicting

5 longer-term capacity for adaption to RT within individuals because it does not represent a typical response over a RT program comprised of multiple training sessions (3-4 per week). Indeed, we reported that following the first training session the acute MPS response is not correlated with muscle hypertrophy after RT in the same individuals (15). There are multiple factors that might explain this observation (15): the short duration of the FSR measurement, subtle differences in proteolysis (7), or inherent variation in the measurement (23); however, we theorize that the most likely explanation for the discordance is that the magnitude and duration of the MPS response to acute RE is highly variable between individuals and can change considerably (11, 24, 29, 30) as RT progresses. It is important to point out that in addition the physiological variability methodological variability and test retest reliability could obscure any relationship between acute MPS and hypertrophy. Muscle hypertrophy can be measured in a number of different ways including fibre area from histological section, lean mass from DXA and cross sectional area of volume from MRI or CT scans. In our previous study (15) hypertrophy was measured by MRI derived muscle because in our experience and that of others (19) variability is ~1%. Much less is known about reproducibility of MPS measure in the same subject and it is conceivable variability inherent in the MPS methodology could obscure any potential relationship. Acute measurements of MPS response can provide important insight into the mechanistic underpinnings of divergent exercise and nutritional manipulations (3, 4, 10, 24, 31). Such measures have shown the ability to discriminate between gross differences in muscle contraction volume (2) and relative fatigue (3, 10) as well as differences in protein quality and amino acid composition (4, 31). Nonetheless, at an individual level a divergent acute response in MPS may be necessary but is not sufficient to conclude that a divergent muscle hypertrophic response will follow and similarly so for RT plus nutrition-induced

6 changes in hypertrophy (14, 15). It is likely that a high degree of intra-individual variation in various factors with repeated exposure to the exercise stimulus. In conclusion, results from acute measures of MPS should continue to be regarded important indicators of the gross-level potential of a given exercise/nutritional intervention; however long term studies are necessary to elucidate the capacity to which an individual will respond in terms of altered phenotype (i.e. increased muscle mass) in response to chronic exposure to a given exercise/nutritional intervention. 125

7 126 References Breen L, Stokes KA, Churchward-Venne TA, Moore DR, Baker SK, Smith K, Atherton PJ, and Phillips SM. Two weeks of reduced activity decreases leg lean mass and induces "anabolic resistance" of myofibrillar protein synthesis in healthy elderly. The Journal of clinical endocrinology and metabolism 98: , Burd NA, Holwerda AM, Selby KC, West DW, Staples AW, Cain NE, Cashaback JG, Potvin JR, Baker SK, and Phillips SM. Resistance exercise volume affects myofibrillar protein synthesis and anabolic signalling molecule phosphorylation in young men. The Journal of physiology 588: , Burd NA, West DW, Staples AW, Atherton PJ, Baker JM, Moore DR, Holwerda AM, Parise G, Rennie MJ, Baker SK, and Phillips SM. Low-load high volume resistance exercise stimulates muscle protein synthesis more than high-load low volume resistance exercise in young men. PloS one 5: e12033, Churchward-Venne TA, Breen L, Di Donato DM, Hector AJ, Mitchell CJ, Moore DR, Stellingwerff T, Breuille D, Offord EA, Baker SK, and Phillips SM. Leucine supplementation of a lowprotein mixed macronutrient beverage enhances myofibrillar protein synthesis in young men: a double-blind, randomized trial. The American journal of clinical nutrition 99: , Cuthbertson D, Smith K, Babraj J, Leese G, Waddell T, Atherton P, Wackerhage H, Taylor PM, and Rennie MJ. Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19: , Glover EI. Immobilisation induces anabolic resistance in human myofibrillar protein synthesis with low and high dose amino acid infusion. The Journal of physiology 24: , Glynn EL, Fry CS, Drummond MJ, Dreyer HC, Dhanani S, Volpi E, and Rasmussen BB. Muscle protein breakdown has a minor role in the protein anabolic response to essential amino acid and carbohydrate intake following resistance exercise. American journal of physiology Regulatory, integrative and comparative physiology 299: R , Hartman JW, Tang JE, Wilkinson SB, Tarnopolsky MA, Lawrence RL, Fullerton AV, and Phillips SM. Consumption of fat-free fluid milk after resistance exercise promotes greater lean mass accretion than does consumption of soy or carbohydrate in young, novice, male weightlifters. The American journal of clinical nutrition 86: , Holm L, Reitelseder S, Pedersen TG, Doessing S, Petersen SG, Flyvbjerg A, Andersen JL, Aagaard P, and Kjaer M. Changes in muscle size and MHC composition in response to resistance exercise with heavy and light loading intensity. J Appl Physiol 105: , Holm L, van Hall G, Rose AJ, Miller BF, Doessing S, Richter EA, and Kjaer M. Contraction intensity and feeding affect collagen and myofibrillar protein synthesis rates differently in human skeletal muscle. American journal of physiology Endocrinology and metabolism 298: E , Kim PL, Staron RS, and Phillips SM. Fasted-state skeletal muscle protein synthesis after resistance exercise is altered with training. The Journal of physiology 568: , Krieger JW. Single vs. multiple sets of resistance exercise for muscle hypertrophy: a metaanalysis. Journal of strength and conditioning research / National Strength & Conditioning Association 24: , Kumar V, Selby A, Rankin D, Patel R, Atherton P, Hildebrandt W, Williams J, Smith K, Seynnes O, Hiscock N, and Rennie MJ. Age-related differences in the dose-response relationship of muscle protein synthesis to resistance exercise in young and old men. The Journal of physiology 587: , Mayhew DL, Kim JS, Cross JM, Ferrando AA, and Bamman MM. Translational signaling responses preceding resistance training-mediated myofiber hypertrophy in young and old humans. J Appl Physiol 107: , 2009.

8 Mitchell CJ, Churchward-Venne TA, Parise G, Bellamy L, Baker SK, Smith K, Atherton PJ, and Phillips SM. Acute post-exercise myofibrillar protein synthesis is not correlated with resistance training-induced muscle hypertrophy in young men. PloS one 9: e89431, Mitchell CJ, Churchward-Venne TA, West DW, Burd NA, Breen L, Baker SK, and Phillips SM. Resistance exercise load does not determine training-mediated hypertrophic gains in young men. J Appl Physiol 113: 71-77, Moore DR, Churchward-Venne TA, Witard O, Breen L, Burd NA, Tipton KD, and Phillips SM. Protein Ingestion to Stimulate Myofibrillar Protein Synthesis Requires Greater Relative Protein Intakes in Healthy Older Versus Younger Men. The journals of gerontology Series A, Biological sciences and medical sciences Murton AJ, Billeter R, Stephens FB, Des Etages SG, Graber F, Hill RJ, Marimuthu K, and Greenhaff PL. Transient transcriptional events in human skeletal muscle at the outset of concentric resistance exercise training. J Appl Physiol (1985) 116: , Nordez A, Jolivet E, Sudhoff I, Bonneau D, de Guise JA, and Skalli W. Comparison of methods to assess quadriceps muscle volume using magnetic resonance imaging. Journal of magnetic resonance imaging : JMRI 30: , Phillips SM. A brief review of critical processes in exercise-induced muscular hypertrophy. Sports Med 44 Suppl 1: 71-77, Phillips SM, Tipton KD, Aarsland A, Wolf SE, and Wolfe RR. Mixed muscle protein synthesis and breakdown after resistance exercise in humans. The American journal of physiology 273: E99-107, Rennie MJ. An introduction to the use of tracers in nutrition and metabolism. The Proceedings of the Nutrition Society 58: , Smith GI, Patterson BW, and Mittendorfer B. Human muscle protein turnover--why is it so variable? J Appl Physiol 110: , Tang JE, Perco JG, Moore DR, Wilkinson SB, and Phillips SM. Resistance training alters the response of fed state mixed muscle protein synthesis in young men. American journal of physiology Regulatory, integrative and comparative physiology 294: R , Timmerman KL, Dhanani S, Glynn EL, Fry CS, Drummond MJ, Jennings K, Rasmussen BB, and Volpi E. A moderate acute increase in physical activity enhances nutritive flow and the muscle protein anabolic response to mixed nutrient intake in older adults. The American journal of clinical nutrition 95: , Wall BT, Snijders T, Senden JM, Ottenbros CL, Gijsen AP, Verdijk LB, and van Loon LJ. Disuse impairs the muscle protein synthetic response to protein ingestion in healthy men. The Journal of clinical endocrinology and metabolism 98: , West DW, Burd NA, Tang JE, Moore DR, Staples AW, Holwerda AM, Baker SK, and Phillips SM. Elevations in ostensibly anabolic hormones with resistance exercise enhance neither traininginduced muscle hypertrophy nor strength of the elbow flexors. J Appl Physiol 108: 60-67, West DW, Kujbida GW, Moore DR, Atherton P, Burd NA, Padzik JP, De Lisio M, Tang JE, Parise G, Rennie MJ, Baker SK, and Phillips SM. Resistance exercise-induced increases in putative anabolic hormones do not enhance muscle protein synthesis or intracellular signalling in young men. The Journal of physiology 587: , Wilkinson DJ, Franchi MV, Brook MS, Narici MV, Williams JP, Mitchell WK, Szewczyk NJ, Greenhaff PL, Atherton PJ, and Smith K. A validation of the application of D2O stable isotope tracer techniques for monitoring day-to-day changes in muscle protein subfraction synthesis in humans. American journal of physiology Endocrinology and metabolism 306: E , Wilkinson SB, Phillips SM, Atherton PJ, Patel R, Yarasheski KE, Tarnopolsky MA, and Rennie MJ. Differential effects of resistance and endurance exercise in the fed state on signalling molecule phosphorylation and protein synthesis in human muscle. The Journal of physiology 586: , 2008.

9 Wilkinson SB, Tarnopolsky MA, Macdonald MJ, Macdonald JR, Armstrong D, and Phillips SM. Consumption of fluid skim milk promotes greater muscle protein accretion after resistance exercise than does consumption of an isonitrogenous and isoenergetic soy-protein beverage. The American journal of clinical nutrition 85: ,