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Hypertrophy and Load – Part II
by: Anoop Balachandran

The last article we discussed microtrauma and why it is essential for hypertrophy, as well as how load is linearly related to microtrauma. In this concluding part, we will look into the endocrine and metabolic factors that are often used to determine load guidelines for optimal hypertrophy.

Endocrine Factors

As the name connotes, growth hormone (GH) is anabolic in nature. The loss of strength and muscle mass characteristic of GH deficient folks, and the reversal in these performance indices upon GH supplementation, clearly reveals its anabolic role (1,2,3). This information, coupled with the presence of greater GH secretion following resistance training, leads to a barrage of GH studies which are worth discussing.

Interestingly, common to all these studies is a greater growth hormone response following moderate loads using shorter rest periods when compared with high loads using longer rest periods (4,5,6). Kraemer et al., for instance, showed that performing a 10 RM with 1 minute rest between sets showed greater GH response than performing a 5 RM with 5 minute rest periods (4). Another study reported that performance of 20 sets of 1RM produced a slight increase in GH, whereas a substantial increase in GH was observed following 10 sets of 10 repetitions with 70% of 1RM (5). Call it coincidence if you like, but the protocol that shows the greatest GH release appears to be that of a typical bodybuilding routine, while the program which showed the least GH response mirrored what we typically consider a powerlifting program.

Although researchers couldn’t find any causal evidence, this GH hypothesis was evidence enough to establish the current load and rest time guidelines for hypertrophy.

But is the evidence really enough? Let’s see: one of the early processes involved in the secretions of GH is the accumulation of metabolic products like lactate (La) and proton (H) in the muscle. The acidic environment in the muscle stimulates sympathetic nerve activity through chemoreceptors, which may send signals to the hypothalamus-pituitary system, and in turn trigger the secretion of GH (6,7). Apparently, the changes in GH seen in most of the studies were in phase with changes in the lactate concentration (4,5). This suggests that metabolic accumulation during exercise is the primary stimulus influencing GH release. For example, Takarada showed a low intensity (20 RM) exercise to cause a 290-fold increase in the concentration of GH when the blood flow was blocked by occlusion (8). This magnitude of increase, even larger than that reported using heavier loads, reveals metabolic accumulation due to occlusion to be primarily responsible for GH release.

Activities that stress the metabolic pathways like hyperventilation, breath holding, hypoxia and even nicotinic acid ingestion have been shown to profoundly influence growth hormone release (9,10). The high correlation of GH and metabolic products is further supported by the decreased GH response following induced alkalosis during cycling (11). And, keep in mind that all these changes in GH are transient: the resting concentration of GH has never been altered by any sort of resistance training (12,13,14).

Researchers began to suspect that raising the resting concentration of GH through supplementation might be the key to inducing hypertrophy. After all, GH is a common ingredient in any bodybuilder’s drug list. As expected, this let lose another flurry of GH supplementation studies. Surprisingly the majority of the studies, whether in young men, older men or athletes, showed little change in muscle fiber size or strength after GH supplementation (15,16,17). The inability of even supraphysiological doses to elicit a hypertrophic response clearly undermines the role these training-induced tiny spikes of GH play in hypertrophy.

The discovery of local growth factors and their central role in hypertrophy was the final blow which shifted the foundation of the growth hormone hypothesis. Studies showed muscle growth even after the depression of circulating GH and IGF-1 levels (19). Worse yet, substantial increase in muscle mass was observed even after the GH axis was surgically interrupted (20,21).

Ironically, after all these counter evidences the repetition bracket of 8-12 is still hailed as the optimum range for hypertrophy- and the same old GH hypothesis is still being quoted in its defense.

Metabolic Factors

Though mechanical factors are essential to resistance training adaptations, metabolic factors have also been shown to play a role in hypertrophy.

The feeling of “pump” or “burn” is associated with the build up of these metabolic products (H, La, P, Cr, and K) in the muscle; the higher the number of reps in a set, the greater their accumulation and effect. Traditionally, studies have used three methods to understand the influence of metabolites on hypertrophy and strength. And, all three methods have revealed conflicting roles for metabolites in hypertrophy.

Eccentric contractions recruit fewer fibers than concentric contractions when using the same load. This distinct metabolic characteristic of contractions is often exploited to examine the importance of high force stress versus metabolic stress on hypertrophy (1,2). The second method involves the manipulation of rest intervals between sets: shorter rest intervals are metabolically more taxing than longer rest intervals (3,4). The occlusion method uses a pressurized cuff to occlude or clog the blood flow to the exercising muscle and in turn also increases the metabolic fatigue (5,6).

Now let’s delve deeper and look at the possible mechanisms by which the metabolic milieu can impact hypertrophy. One possibility is that the ischemic condition and/or the metabolic changes in the muscle could lead to a greater recruitment of the fast twitch muscle fibers (Type 2). This is quite evident from the greater EMG activity recorded in the occlusion studies. For instance, Moore and his team specifically investigated the neuromuscular activity accompanying occlusion and showed that there is an early activation of Type 2 fibers for the occlusive group compared to the non-occlusive group (5). Another study showed the EMG activity in the low intensity exercise (40% 1RM) with occlusion to be almost equal to that in the high intensity exercise (80% 1RM) without occlusion (6).


This, along with the greater vulnerability of Type 2 fibers to injury and subsequent hypertrophy might very well be responsible for the greater hypertrophy and strength observed in some of the occlusion and rest interval studies using lighter loads.

Muscular hypertrophy is a combination of both sarcoplasmic and sarcomeric hypertrophy. In contrast to the actual growth of muscle fibers as in sarcomeric hypertrophy, sarcoplasmic hypertrophy involves the “swelling” of the muscle mainly via increase in water and glycogen accumulation without any change in strength. As evident from the occlusion studies, this increase is prompted largely by the accumulation of metabolites. For instance, exercise in the occluded group showed greater glycogen accumulation than in the non-occluded group (7). Additionally, studies showed glucose uptake to be enhanced in response to hypoxic conditions (8,9).

The increase in sarcoplasmic volume certainly contributes to overall hypertrophy and might partly explain the increase in muscle mass observed with higher rep training. And it is likely that comparison between repetition studies is distorted, since the current methods for measuring fiber size are incapable of identifying the contribution of sarcoplasmic hypertrophy to the overall muscle size.

Another mechanism which seems to suggest a role for metabolites in hypertrophy is the production of free radicals. It has been shown that muscular xanthase activity is elevated in hypoxic conditions and produces ROS (free radicals) during subsequent reperfusions. These free radicals via ischemic/reperfusion injuries have been shown to promote growth in smooth and cardiac muscles (11). The periodic application of occlusive stimulus, without any exercise stimulus, attenuates the disuse atrophy of leg muscles. This is possibly due to the direct effect free radicals have on muscle protein synthesis (10).

All said, hypertrophy through metabolic accumulation almost always occurred in conjunction with some sort of load training. Further, the importance of load is clearly revealed by the greater need for heavier loads in the strength continuum as opposed to the endurance continuum. Hypertrophy credits only a secondary role to metabolic fatigue.

Practical Considerations

It is well established that load is the primary stimulus for strength. And if you cared to notice, I’ve been trying to convey how load is the primary stimulus for hypertrophy too. The greater the load, the greater your strength and muscle gains. Simply put, you can expect greater gains in strength and hypertrophy by using your 1RM for 10 reps than using your 10RM for 10 reps.

So a fair question would be: are strength increases a good measure of muscle growth? I would say that strength is a yard stick for muscle growth, as well as the BEST indicator of progress one has in a hypertrophy routine. This might seem in stark contrast to those funky neural adaptation programs claiming to selectively target hypertrophy and leave out strength or vice versa.

The expression of strength is a blend of neural and muscular adaptations. Neural adaptations are in the form of increased activation, enhanced supraspinal output, intermuscular and intramuscular coordination, antagonist co-activation and so on (1,2). Muscular adaptations can not only show up in the form of increased muscle mass but also in the form of subtle architectural changes in pennation angle, muscle fascicle length and specific tension (3,4). However, most of us have missed that all these neural and architectural adaptations can only contribute so much so far, and beyond those “optimizations” muscle size becomes the leading and indeed the only adaptation that will allow continued gains in strength.

According to the scheme proposed by D. G Sale–a pioneer in field of neural adaptations–neural mechanisms largely contribute to strength gains during the early phase of training, after which muscular adaptations dominate (1). The same can be inferred from his recent remarks: “After years of training, I suspect that there is little or no neural adaptation that can increase strength further, apart from a change in technique. Strength in the highly trained state is almost entirely a function of muscle mass. This would explain why athletes ultimately resort to anabolic steroids – increasing muscle mass is the only way to increase strength further (Personal Communication).”

The prevailing belief that powerlifters target the nervous system more so than the muscles by using low reps is yet to be proved by science. It is clear that heavy load around the 1RM causes higher fatigue and requires longer recovery periods than a lighter load. The high fatigue experienced is not just due to nervous system fatigue alone; disruptions in the contractile system are equally responsible (5,6). Powerlifting, often seen as a “little-to-do-with-muscle-event”, has been shown to indeed be a function of muscle mass, and lifting performance has been shown to be limited by the ability to accumulate muscle mass (3). And once these elite lifters hit their genetic limits with regard to muscle mass, strength increases are marginal at best (7).

Even the CNS fatigue which seems to be the buzz word these days is not just a neural phenomenon as it sounds. Overtraining as most of us might have experienced hits in the form of generalized fatigue, depression, muscle and joint pain, loss of appetite, decreased performance, decreased muscular strength and so forth. These signs/symptoms of overtraining are often blamed as a neural phenomenon. But according to the cytokine hypothesis of overtraining, repetitive trauma to the musculoskeletal system due to high intensity/volume training is the predominant cause of overtraining (8,9). That is, the many physiological and behavioral signs associated with overtraining syndrome are basically triggered by a musculoskeletal injury.

But the question remains: If strength is highly correlated with muscle size, what about those bodybuilders who are big yet not strong?


First and foremost, elite class bodybuilders are dipped in drugs. And drugs lie right to your face. Testosterone and GH administration have shown to increase retention of fluid (water/salt) within the muscle that would cause an enlargement of the muscle fibers with little strength change (15,16). Second, testosterone is shown to cause changes in strength by altering the muscle architecture in the absence of any major increase in muscle mass (4,14). And when on test you can always compromise on load unlike the natural trainees. It is now becoming increasingly clear that testosterone promotes its anabolic effects primarily through an increase in satellite cell proliferation and myonuclear number (10,4). Sadly for natural trainees the only viable option to activate satellite cell is through load mediated injury.

More important, direct comparison with highly trained athletes can be misleading because the neural patterns have probably matured in these individuals. Thus without major neural changes, the force per cross sectional area remains the same or decreased compared to less trained individuals. Further, some of the incongruity surrounding strength with enlarging muscle can be accounted by changes within the muscle cells like enlarged interstitial space, and decreased protein concentration (11). So, don’t let appearances lead your conclusions.

Whether you hit a muscle group thrice a week or once a week, whether you perform 1 set or 6 sets, high rep or low rep, if strength is climbing, stick with it. The tenets of typical bodybuilding routines like repetitions of 8-12, sets to failure, changing exercises often, and short rest intervals were all laid on the faulty premise that not load but fatigue is the primary stimulant for hypertrophy.

Opt for a periodized routine (cycling of loads to manage fatigue) built on a few basic and a few auxiliary exercises with adequate rest between sets. Additionally, stick to around 5 reps per set, and terminate each set 1 or 2 reps short of failure. A drop set of 15-20 reps right after your last work set would work well to create metabolic fatigue without sacrificing load.

Anyhow, to make a long story short, the ultimate hypertrophy routine will be the ultimate strength routine.

Good luck.


Endocrine Factors

1. de Boer H, Blok GJ, Van der Veen EA.Clinical aspects of growth hormone deficiency in adults. Endocr Rev. 1995 Feb;16(1):63-86

2. RC, Salomon F, Wiles CM, Sonksen PH.Skeletal muscle performance in adults with growth hormone deficiency Horm Res. 1990;33 Suppl 4:55-60

3. Abdul Shakoor SK, Shalet SM.Effects of GH replacement on metabolism and physical performance in GH deficient adults. J Endocrinol Invest. 2003 Sep;26(9):911-8.

4. Kraemer WJ, Marchitelli L, Gordon SE, Harman E, Dziados JE, Mello R, Frykman P, McCurry D, Fleck SJ. Hormonal and growth factor responses to heavy resistance exercise protocols.J Appl Physiol. 1990 Oct;69(4):1442-50

6. Kraemer WJ, Gordon SE, Fleck SJ, Marchitelli LJ, Mello R, Dziados JE, Friedl K, Harman E, Maresh C, Fry AC. Endogenous anabolic hormonal and growth factor responses to heavy resistance exercise in males and females Int J Sports Med. 1991 Apr;12(2):228-35.

5. Hakkinen K, Pakarinen A. Acute hormonal responses to two different fatiguing heavy-resistance protocols in male athletes.J Appl Physiol. 1993 Feb;74(2):882-7.

6. Victor RG, Seals DR. Reflex stimulation of sympathetic outflow during rhythmic exercise in humans.Am J Physiol. 1989 Dec;257(6 Pt 2):H2017-24.

7. Gosselink KL, Grindeland RE, Roy RR, Zhong H, Bigbee AJ, Grossman EJ, Edgerton VR.Skeletal muscle afferent regulation of bioassayable growth hormone in the rat pituitary.J Appl Physiol. 1998 Apr;84(4):1425-30.

8) Takarada, Y., Nakamura, Y., Aruga, S., Onda, T., Miyazaki, S., & Ishii, N. (2000). Rapid increase in plasma growth hormone after low-intensity resistance exercise with vascular occlusion. Journal Applied Physiology, 88 (1), 61-65.

9) Djarova, T., Ilkov, A., Varbanova, A., Nikiforova, A., & Mateev, G. (1986). Human growth hormone, cortisol, and acid-base balance changes after hyperventilation ad breath-holding. International Journal of Sports Medicine, 7(6), 311-5.

10) Murray, R., Bartoli, W. P., Eddy, D. E., & Horn, M. K. (1995). Physiological and performance responses to nicotinic-acid ingestion during exercise. Medicine and Science in Sports and Exercise, 27(7), 1057-62.

11) Gordon, S.E., Kraemer, W. J., Vos, N. H., Lynch, J. M., & Knuttgen, H. G. (1994). Effect of acid-base balance on the growth hormone response to acute high-intensity cycle exercise. Journal of Applied Physiology, 76(2), 821-9.

12) Craig, B. W., R. Brown, and J. Everhart. Effects of progressive resistance training on growth hormone and testosterone levels on young and elderly subjects. Mech. Ageing Dev. 49: 159-169, 1989

13) Häkkinen, K., A. Pakarinen, M. Alen, and P. V. Komi. Serum hormones during prolonged training of neuromuscular performance. Eur. J. Appl. Physiol. 53: 287-293, 1985.

14) McCall GE, Byrnes WC, Fleck SJ, Dickinson A, Kraemer WJ. Acute and chronic hormonal responses to resistance training designed to promote muscle hypertrophy Can J Appl Physiol. 1999 Feb;24(1):96-107

15) J, Kjaer M. GH administration changes myosin heavy chain isoforms in skeletal muscle but does not augment muscle strength or hypertrophy, either alone or combined with resistance exercise training in healthy elderly men. J Clin Endocrinol Metab. 2002 Feb;87(2):513-23.

16) Yarasheski, K. E., Campbell, J. A., Smith, K., Rennie, M. J., Holloszy, J. O., & Bier D. M. (1992). Effect of growth hormone and resistance exercise on muscle growth in young men. American Journal of Applied Physiology, 262(3), 261-7.

17) Yarasheski, K. E., Zachweija, J. J., Angelopoulos, T. J., & Bier, D. M. (1993). Short-term growth hormone treatment does not increase muscle protein synthesis in experienced weight lifters. Journal of Applied Physiology, 74(6), 3073-6.

18) Yarasheski, K. E., Zachwieja, J. J., Campbell, J. A., & Bier, D. M. (1995). Effect of growth hormone and resistance exercise on muscle growth and strength in older men. American Journal of Applied Physiology, 268(2), E268-E276.

19) Adams GR, Haddad F.The relationships among IGF-1, DNA content, and protein accumulation during skeletal muscle hypertrophy. J Appl Physiol. 1996 Dec;81(6):2509-16.

20) Zanconato S, Moromisato DY, Moromisato MY, Woods J, Brasel JA, Leroith D, Roberts CT Jr, Cooper DM.Effect of training and growth hormone suppression on insulin-like growth factor I mRNA in young rats. J Appl Physiol. 1994 May;76(5):2204-9

21) Bates PC, Loughna PT, Pell JM, Schulster D, Millward DJ.Interactions between growth hormone and nutrition in hypophysectomized rats: body composition and production of insulin-like growth factor-I. J Endocrinol. 1993 Oct;139(1):117-26.

Metabolic Factors

1) Smith RC, Rutherford OM The role of metabolites in strength training. I. A comparison of eccentric and concentric contractions. Eur J Appl Physiol Occup Physiol. 1995;71(4):332-6.

2) Hortobagyi T, Hill JP, Houmard JA, Fraser DD, Lambert NJ, Israel RG. Adaptive responses to muscle lengthening and shortening in humans. J Appl Physiol. 1996 Mar;80(3):765-72.

3) Rooney KJ, Herbert RD, Balnave RJF. Fatigue contributes to the strength training stimulus Med Sci Sports Exerc. 1994 Sep;26(9):1160-4.

4) Folland, J. P, Irish, C. S., Roberts, J. C., Tarr, J. E., and Jones, D. A. (2002). Fatigue is not a necessary stimulus for strength gains during resistance training. Br J Sports Med 2002;36:370-373.

5) Moore, D. R, Burgomaster, K. A, Schofield, L. M, Gibala, J. M, Sale, D. G, and Phillips, S. M. (2004). Neuromuscular adapataions in human muscle following low intensity resistance training with vascular occlusion. European Journal of Applied Physiology, 92, 399-406.

6) Takarada Y, Takazawa H, Sato Y, Takebayashi S, Tanaka Y, Ishii N.Effects of resistance exercise combined with moderate vascular occlusion on muscular function in humans.J Appl Physiol. 2000 Jun;88(6):2097-106.

7) Burgomaster, K. A, Moore, D. R., Schofield LM, Phillips SM, Sale DG, Gibala MJ.(2003).Resistance training with vascular occlusion: metabolic adaptations in human muscle. 35(7),1203-8.

8) Azevedo, J. L. Jr, Carey, JO, Pories WJ, Morris PG, Dohm GL. (1995). Hypoxia stimulates glucose transport in insulin-resistant human skeletal muscle.Diabetes. ;44(6):695-8.

9) Fluckey JD, Ploug T, Galbo H. Mechanisms associated with hypoxia- and contraction-mediated glucose transport in muscle are fibre-dependent.Acta Physiol Scand. 1999 Sep;167(1):83-7.

10) Takarada Y, Takazawa H, Ishii N. Applications of vascular occlusion diminish disuse atrophy of knee extensor muscles. Med Sci Sports Exerc. 2000 Dec;32(12):2035-9.

11) Suzuki YJ, Ford GD. Redox regulation of signal transduction in cardiac and smooth muscle. Mol Cell Cardiol. 1999 Feb;31(2):345-53. Review.

Practical Considerations

1) Sale , D. G. Neural adaptation to resistance training. Med Sci Sports Exerc. 1988 Oct;20(5 Suppl):S135-45. Review.

2) Enoka, R. (2002). Neuromechanics of human movement. Human kinetics.

3) Brechue WF, Abe T.The role of FFM accumulation and skeletal muscle architecture in powerlifting performance. Eur J Appl Physiol. 2002 Feb;86(4):327-36.

4) Herbst KL, Bhasin S.Testosterone action on skeletal muscle. Curr Opin Clin Nutr Metab Care. 2004 May;7(3):271-7. Review.

5) Raastad T, Hallen J.Recovery of skeletal muscle contractility after high- and moderate-intensity strength exercise. Eur J Appl Physiol. 2000 Jun;82(3):206-14

6) Fry AC, Kraemer WJ, van Borselen F, Lynch JM, Marsit JL, Roy EP, Triplett NT, Knuttgen HG. Performance decrements with high-intensity resistance exercise overtraining. Med Sci Sports Exerc. 1994 Sep;26(9):1165-73.

7) Hakkinen K, Pakarinen A, Alen M, Kauhanen H, Komi PV.Neuromuscular and hormonal adaptations in athletes to strength training in two years.J Appl Physiol. 1988 Dec;65(6):2406-12.

8) Smith, L. L.Tissue trauma: the underlying cause of overtraining syndrome? J Strength Cond Res. 2004 Feb;18(1):185-93. Review.
9) Smith. L. L. Cytokine hypothesis of overtraining: a physiological adaptation to excessive stress? Med Sci Sports Exerc. 2000 Feb;32(2):317-31.

10) Kadi F. Adaptation of human skeletal muscle to training and anabolic steroids. Acta Physiol Scand Suppl. 2000 Jan;646:1-52.

11) Kandarian SC, White TP.Force deficit during the onset of muscle hypertrophy. J Appl Physiol. 1989 Dec;67(6):2600-7.

12) Forbes G. B. Exercise and lean weight: the influence of body weight.
Nutr Rev. 1992 Jun;50(6):157-61. Review.

13) Forbes G. B. Perspectives on body composition. Curr Opin Clin Nutr Metab Care. 2002 Jan;5(1):25-30. Review.

14) Storer TW, Magliano L, Woodhouse L, Lee ML, Dzekov C, Dzekov J, Casaburi R, Bhasin S.estosterone Dose-Dependently Increases Maximal Voluntary Strength and Leg Power, but Does Not Affect Fatigability or Specific Tension. Clin Endocrinol Metab. 2003 Apr;88(4):1478-85.

15) Creutzberg, Eva C.; Schols, Annemie M.W.J. Anabolic Steroids. Current Opinion in Clinical Nutrition & Metabolic Care. 2(3):243-253, May 1999.

16) Yarasheski, K. E., Zachwieja, J. J., Campbell, J. A., & Bier, D. M. (1995). Effect of growth hormone and resistance exercise on muscle growth and strength in older men. American Journal of Applied Physiology, 268(2), E268-E276.