Anabolic Resistance in Hypertrophy
Athletes and recreational weightlifters often aim to maximize the hypertrophic response to exercise in hope that it will translate to an increase in performance or a better physique. If you read something like this then you would think that you can get anabolic resistance from bulking. This simply isn’t the case. This is a perfect of example of people extrapolating data from science the wrong way. I do think there is some truth in the body weight set point theory (1), but most people who suffer from anabolic resistance are either aging or obese (see more below). Furthermore, it is well-known that the best way to increase muscle mass is by increasing calories in combination with resistance exercise not just eating as much as you can and hoping for the best. Moreover, there is no evidence to show that insulin resistance can occur in a matter of weeks in an otherwise healthy person.
Anabolic Resistance in Aging
I previously wrote about sarcopenia, which results in a functional decline accompanied by physical disability in people over age 60. One of the factors of this decline is anabolic resistance. This is defined as the inability for muscle to respond to anabolic stimuli. Simply, the body is unable to maintain protein turnover in response to nutrition and exercise. Why should you care, you say? Well, the World Health Organization estimates that the expansion of the population over age 60 will more than triple by 2050 (2). Importantly, older adults play a role in care-giving, volunteering, and many other social aspects. We need to start implementing steps to help our bodies over the course of our entire life, not just during college.
A loss in muscle mass results from an imbalance between the rates of protein synthesis and breakdown. It is established that dietary protein causes increases in muscle mass by increasing muscle protein synthesis (MPS). Furthermore, insulin has been proven to stimulate MPS and also participate in muscle amino acid uptake (3). However, it is controversial whether the loss of muscle mass in sarcopenia is due from a decrease in MPS or an increase in muscle protein breakdown.
A study by Guillet and colleagues showed that the ability of insulin and branched chain amino acids (protein) to initiate protein translation was decreased in older individuals compared to young subjects. This and other evidence has shown that that the ability to increase muscle mass becomes harder with age. There is also some thought that inflammation may play a key role in the development of sarcopenia, especially through anabolic resistance (4). Inflammation is viewed as chronic in older individuals. Furthermore, it is characterized by increased production of cytokines and acute-phase proteins. Some scientists refer to this as “inflammaging”. Below you can see a graph comparing muscle loss and age in various diseases. For example, if you add a disease such as diabetes on top of aging, you can expect to see drastic decreases in muscle mass over time. This is important because muscle mass is associated with quality of life and independence.
The accelerated rate of sarcopenia via various behaviors and diseases depicted based on estimates from the literature. As you can see, lifelong resistance exercises decreases the loss in muscle over time.
It has recently been shown that anabolic resistance can occur during obesity. In one study it was found that protein metabolism was impaired and there was a reduced post-absorptive protein turnover in obese men compared to controls (5). Another study used genetically obese rats to show that old rats were more prone to ectopic muscle lipid accumulation than young rats, leading to decreased muscle protein anabolism (6). In addition, it has been shown that sarcopenic obesity is associated with an enhancement of basal protein synthesis rates and that insulin-resistant skeletal muscle is refractory to the anabolic stimulus of resistance exercise (7). These studies, in combination, shed light on the basis of anabolic resistance in obesity. The exact mechanism is unknown, but there is ample evidence that obesity plays a role in muscle mass. There are more studies needed to understand what is happening at the molecular signaling level.
The story of anabolic resistance is very important in the battle to retain muscle mass with aging and obesity. The use of animal and rodent models has allowed for a translational approach to determining the mechanisms behind it. I think it is also important to point out that there is a lack of general consensus amongst laboratories as to the presence of anabolic resistance in elderly individuals (8). These differences may be due to methodological differences, such as the timing of muscle biopsies, muscle protein pool studied, the precursor pool used to determine muscle protein synthesis, or indirect measurements. Interestingly, from an intervention point, diet and exercise could be tailored specifically to optimize muscle mass and function (9). However, when diet and exercise are less effective such as those over age 80 then the development of a therapeutic agent could be beneficial.
2. WHO. Ageing (online). 2008. http://www.who.int/topics/ageing/en.
3. Haran PH, Rivas DA, Fielding RA. Role and potential mechanisms of anabolic resistance in sarcopenia. Journal of Cachexia, Sarcopenia and Muscle. 2012;3(3):157-162. doi:10.1007/s13539-012-0068-4.
3. Biolo G, Declan Fleming RY, Wolfe RR. Physiologic hyperinsulinemia stimulates protein synthesis and enhances transport of selected amino acids in human skeletal muscle. J Clin Invest. 1995;95:811–9.
4. Peake J, Della Gatta P, Cameron-Smith D. Aging and its effects on inflammation in skeletal muscle at rest and following exercise induced muscle injury. Am J Physiol Regul Integr Comp Physiol. 2010;298:R1485–95.
5. Guillet C, Delcourt I, Rance M, Giraudet C,Walrand S, Bedu M, et al. Changes in basal and insulin and amino acid response of whole body and skeletal muscle proteins in obese men. J Clin Endocrinol Metab. 2009;94:3044–50.
6. Tardif, Nicolas, Jérôme Salles, Christelle Guillet, Joan Tordjman, Sophie Reggio, Jean-François Landrier, Christophe Giraudet, et al. “Muscle Ectopic Fat Deposition Contributes to Anabolic Resistance in Obese Sarcopenic Old Rats through eIF2α Activation.” Aging Cell 13, no. 6 (December 2014): 1001–11. doi:10.1111/acel.12263.
7. Nilsson, Mats I., Justin P. Dobson, Nicholas P. Greene, Michael P. Wiggs, Kevin L. Shimkus, Elyse V. Wudeck, Amanda R. Davis, Marissa L. Laureano, and James D. Fluckey. “Abnormal Protein Turnover and Anabolic Resistance to Exercise in Sarcopenic Obesity.” FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology 27, no. 10 (October 2013): 3905–16. doi:10.1096/fj.12-224006.
8. Burd, Nicholas A., Benjamin T. Wall, and Luc J. C. van Loon. “The Curious Case of Anabolic Resistance: Old Wives’ Tales or New Fables?” Journal of Applied Physiology 112, no. 7 (April 1, 2012): 1233–35. doi:10.1152/japplphysiol.01343.2011.
9. Breen and Phillips Nutrition & Metabolism 2011, 8:68