This article begins a multi-part series discussing the growing problem of sarcopenia in our aging population. We will discuss our current understanding of sarcopenia, ways to identify it, and how to treat (and hopefully, prevent) it most effectively. This series is meant to complement this fantastic lecture given by Dr. Jonathon Sullivan (M.D., Starting Strength Coach), in which he presented his model of the “Sick Aging Phenotype” characterized by 1) sarcopenia/frailty, 2) the metabolic syndrome, and 3) polypharmacy/medical dependence. It is highly recommended that you watch his lecture in addition to this article, which will focus primarily on the first criterion: Sarcopenia.
It has long been recognized that aging brings with it, among other things, a progressive decrease in muscle mass and a change in fat distribution. The dramatic increase in our aging population has brought to light the consequences of these changes, spurring a surge in geriatrics research. A quick PubMed query- shows that just 15 papers were published on Sarcopenia in 1999, compared to 628 in 2014, with a similar increase is seen for the term “Frailty.” Sarcopenia and frailty are increasingly recognized as a critical underlying piece of the “puzzle” of aging, and they have such deep influences on morbidity and mortality that it is in our interest to learn about it, recognize it, and fight it, both as individuals and as a society.
Originally, sarcopenia (literally, “poverty of flesh”) was simply defined as an “excessive loss of muscle mass,” analogous to the well-established clinical entity known as “osteopenia” (progressive loss of bone mass en route to osteoporosis) (1). The implication being, of course, that a loss of muscle mass implies a proportional loss of strength and overall function. But although the relationship between muscular force production and muscle size (more formally cross-sectional area) is well-established for younger individuals, this relationship is not as consistent in the aging population (2). In fact, for weight-stable individuals, the age-related decline in strength often exceeds changes in physical muscle size for reasons we will discuss later. The original definition for sarcopenia was therefore considered inadequate, and two new criteria were proposed – in addition to having low muscle mass, a sarcopenic individual also demonstrates a loss of strength or physical performance. The term “dynapenia” has been used to refer to the loss of strength or power, but hasn’t really caught on*.
*Editor’s note: Perhaps gainzZzapenia will have better luck?
So, sarcopenia refers to a syndrome of “progressive and generalized loss of skeletal muscle mass and strength.” (3) It is a condition with significant consequences such as; immobility, falls, fractures, injuries, and an inability to carry out activities of daily living that takes away an individual’s independence. It also has metabolic consequences related to insulin resistance, diabetes, and cardiovascular disease. Muscle mass is the largest reservoir of protein and amino acids in the body, the depletion of which also leaves the body with little reserve capacity in case of acute illness or injury. And of course, ALL of these consequences increase overall risk of death. So, starting with the first criterion, how does this state of low muscle mass actually come to be?
At it’s most fundamental and intuitive level, loss of skeletal muscle mass occurs due to an imbalance between protein synthesis and protein breakdown, also known as proteolysis. (4). How and why does this imbalance develop? This is where things get a bit more complicated. Let’s start with the protein breakdown side of the equation.
Protein Breakdown: What kinds of things affect rates of proteolysis? (Please keep in mind that an analysis of these mechanisms could each fill a textbook, so I’ll be covering the “biggest” causes here, simplifying and summarizing as needed.)
1. Disuse atrophy is a well-known phenomenon, and falls in the “common sense” category for most people. Astronauts returning from space are the extreme example of disuse atrophy, where a gravity-free environment results in the complete mechanical unloading of their musculoskeletal system. Depending on length of time spent in this unloaded state, many astronauts have returned to earth sarcopenic and osteopenic (if not fully osteoporotic). Just five days of microgravity is enough to reduce muscle cross-sectional area and force production in astronauts (5)! For those of us stuck here on Earth, disuse atrophy typically results from a sedentary lifestyle or other reasons for prolonged immobilization (hospitalization, bedrest, etc.). As lifters, we understand Hans Selye’s General Adaptation Syndrome – that is, the stress-adaptation-recovery cycle that governs our homeostatic existence. In the same way that stressing our muscles disrupts homeostasis to induce an adaptation (i.e. getting stronger), the removal of such stressors also acts as a “disruptor” of homeostasis, and an commensurate adaptation (i.e. getting weaker) occurs. On a cellular level, atrophy is cell shrinkage due to the loss of organelles, proteins, and cytoplasm. The mechanisms of disuse atrophy are under active research, and include the ubiquitin/proteasome pathway (the “cellular garbage man” that tags cellular components for degradation), the autophagy/lysosome system, and crosstalk between signaling pathways such as IGF1, Akt/mTOR, myostatin, and glucocorticoids (cortisol), among many others (6,7). To make matters worse, disuse atrophy is characterized by the preferential atrophy of our stronger, more powerful Type 2 (“fast-twitch”) muscle fibers (compared to weaker, smaller type 1 “slow-twitch” fibers). This is because we use our type 2 fibers mainly for high-intensity activity, whereas type 1 fibers are used more regularly for activities of daily living and low-intensity activity such as walking (3). This is just one of the many reasons why recommendations of walking as a main form of exercise are wholly inadequate* – it is not of sufficient intensity to make your body maintain its fast-twitch muscle! Fortunately, resistance training of sufficient quality and intensity is enough to reverse this process (to a degree), bringing the powerful type 2 fast-twitch fibers back to life! (3a)
This image shows a cross-section of muscle tissue, using a particular stain to differentiate slow-twitch (lighter) from fast-twitch (darker) muscle fibers. The dark-staining fibers appear shrunken compared to the more plump lighter-staining fibers; this reflects a selective atrophy of the more powerful type 2 (fast-twitch) muscle fibers. This is what it looks like to lose your gainzZz, folks. Be afraid.
2. Nutritional changes often occur due to a physiologic “anorexia of aging.” This refers to a general decrease in appetite that prevents appropriate compensation for acute and chronic undereating. This phenomenon is an independent risk factor for sarcopenia, especially among the very old (8,9). It is thought to be mediated by several physiologic changes in appetite-regulating neurohormones (Neuropeptide Y, CCK, ghrelin, etc.) and their feedback effects (10). Decreased protein and total energy intake results in loss of both fat and lean mass, which not only contributes to sarcopenia and frailty, but also chips away at physiologic reserves that are helpful in case of acute illness. This situation worsens health outcomes, whether in otherwise healthy aging individuals or in the setting of disease-related cachexia (more on this later). In a way, “hitting your macros” is just as important as an old-timer as it is while you’re young!
3. Loss of motor neuron endplates is an age-related process that contributes to both the loss of muscle mass (sarcopenia criterion #1) as well as impaired muscle function (criterion #2) (11,12,13). Motor neuron endplates can be thought of as “electrical outlets” where nerves “plug in” to muscles to activate them. Each nerve sends out a number of branches to innervate individual muscle fibers making up a single motor unit. As “outlets” to the muscle are gradually lost, the muscle becomes more difficult to “turn on,” leaving it in a relative state of disuse that triggers atrophy (as discussed above). This process, once again, preferentially affects the more powerful type 2 (“fast-twitch”) muscle fibers. Occasionally these “lost” type 2 fibers can become re-innervated (get “plugged back in”) from collateral branches of a nerve controlling a type 1 (“slow-twitch”) motor unit. Since all muscle fibers contained in a single motor unit must be of the same fiber type, when this old type 2 fiber wants to join the motor unit of type 1 fibers, it has to switch types to “fit in”. This, unfortunately, means that your once powerful, juicy type 2 fibers must transform into weaker, less powerful type 1 fibers to survive in their new home. This fiber-type switching may not necessarily affect total muscle size, but it does diminish overall strength and performance by shifting the composition of a particular muscle from mostly “fast-twitch” fibers to a greater proportion of “slow-twitch” fibers.
This cross-section of muscle tissue shows large, plump muscle fibers with a focal area of atrophy (~11:00 section of image) characterized by shrunken and condensed fibers. This is the result of denervation injury – the nerve stimulating these particular fibers has been damaged or lost. These particular muscle fibers literally “won’t fire”… unlike your glutes.
- Hormonal changes can contribute to sarcopenia, and these changes can be exacerbated by aging, nutritional status, comorbid diseases, and obesity (14). For example, among testosterone’s many roles is the maintenance of muscle satellite cells; these little guys surround normal muscle cells (myocytes) and are activated by exercise or injury to produce new muscle cells/nuclei, or to repair existing muscle tissue (15,16,17). Think of them as gainzZz precursors; they are self-renewing stem cells important for maintaining, building, and repairing muscle tissue by producing new myonuclei (although satellite cell-independent mechanisms of hypertrophy have also been described). As testosterone declines with age, satellite cell function declines with it, though they can still be stimulated by other means (like training). Testosterone (and other androgens) have a multitude of other relevant effects on skeletal muscle tissue, including inhibition of myostatin signaling (which normally “reins in” muscle growth) (18). Other important hormones include thyroid hormone (deficiency of which can cause a myopathy), Vitamin D, the GH/IGF1 axis, and glucocorticoids. Vitamin D is a particularly interesting hormone-like molecule; its recent popularity in the supplement world was equally matched by skepticism in the medical community for improvement in health outcomes. However, current research does appear to show that the Vitamin D Receptor (VDR) is intimately involved in skeletal muscle signaling and regulation; that said, to what degree it produces clinically significant differences in outcomes remains to be conclusively demonstrated (19). At this point in time, most guidelines for the nutritional management of sarcopenia do include vitamin D supplementation as part of the treatment approach, given its safety profile and low cost (compared to, say, anabolic steroids) (20).
- Comorbid diseases such as the metabolic syndrome, autoimmunity, atherosclerosis, and many others produce a chronically “pro-inflammatory” environment in their body. This is due to a cascade of chemicals known as “cytokines” such as interleukins, interferons, and tumor necrosis factor that mediate a vast number of effects. In addition to triggering protein breakdown (e.g. via NFkB signaling) and muscle cell death, they are also able to inhibit anabolic signaling (e.g. from Insulin-like growth factors) (21,22). The most extreme example of this situation is known medically as “cachexia,” a severe wasting condition associated with diseases such as cancer, HIV/AIDS, and chronic kidney disease, to list a few. This is similarly thought to be mediated in part by inflammatory cytokines; in fact, tumor necrosis factor is also known as “cachexin” for this very reason. Patients with disease-related cachexia have overall poorer outcomes than those without the cachexia syndrome, and treatment of cachexia itself is therefore also an active area of research. Note that sarcopenia is always a feature of cachexia, but the reverse is, fortunately, not always true. To summarize this topic, chronic systemic inflammation is not conducive to optimal gainzZz™.
To summarize, the major contributors to the loss of skeletal muscle protein include disuse, poor nutrition, neuromuscular changes, hormonal status, and chronic inflammation due to comorbid disease.
In the next article we’ll discuss determinants of skeletal muscle protein synthesis (also known as gainzZz), plus a few other factors that decrease muscle function in sarcopenia.
(1) Biomarkers of sarcopenia in clinical trials—recommendations from the International Working Group on Sarcopenia. J Cachexia Sarcopenia Muscle (2012) 3:181–190.
(2) The loss of skeletal muscle strength, mass, and quality in older adults: The health, aging and body composition study. J Gerontol A Biol Sci Med Sci 2006; 61: 1059–64.
(3) Sarcopenia: an undiagnosed condition in older adults. Current consensus definition: prevalence, etiology, and consequences. International working group on sarcopenia. J Am Med Dir Assoc. 12(4): 249–256.
(3a) The decline in skeletal muscle mass with aging is mainly attributed to a reduction in type II muscle fiber size. Exp Gerontol. 2013 May;48(5):492-8.
(4) Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing. 2010 Jul;39(4):412-23.
(5) Front Physiol. 2013; 4: 134. Do we age faster in absence of gravity?
(6) Cellular and molecular mechanisms of muscle atrophy. Disease Models & Mechanisms 6, 25-39 (2013)
(7) Skeletal muscle wasting with disuse atrophy is multi-dimensional: the response and interaction of myonuclei, satellite cells and signaling pathways. Front Physiol. 2014 Mar 17;5:99.
(8) Anorexia of aging: a modifiable risk factor for frailty. Nutrients. 2013 Oct 14;5(10):4126-33.
(9) Association of anorexia with sarcopenia in a community-dwelling elderly population: results from the ilSIRENTE study. Eur J Nutr. 2013 Apr;52(3):1261-8.
(10) Gastrointestinal hormones: the regulation of appetite and the anorexia of ageing. J Hum Nutr Diet. 2012 Feb;25(1):3-15.
(11) Motoneuron loss is associated with sarcopenia. J Am Med Dir Assoc. 2014 Jun;15(6):435-9.
(12) The Motor Unit Number Index (MUNIX) in sarcopenic patients. Exp Gerontol. 2013 Apr;48(4):381-4.
(13) Interrelationship between muscle strength, motor units, and aging. Exp Gerontol. 2013 Sep;48(9):920-5.
(14) Sarcopenia and age-related endocrine function. Int J Endocrinol. 2012;2012:127362.
(15) Muscle satellite cell heterogeneity and self-renewal. Front Cell Dev Biol. 2014 Jan 30;2:1.
(16) Testosterone-induced muscle hypertrophy is associated with an increase in satellite cell number in healthy, young men. Am J Physiol Endocrinol Metab. 2003 Jul;285(1):E197-205.
(17) Effects of testosterone supplementation on skeletal muscle fiber hypertrophy and satellite cells in community-dwelling older men. J Clin Endocrinol Metab. 2006 Aug;91(8):3024-33.
(18) Testosterone supplementation reverses sarcopenia in aging through regulation of myostatin, c-Jun NH2-terminal kinase, Notch, and Akt signaling pathways. Endocrinology. 2010 Feb;151(2):628-38.
(19) Vitamin D and its role in skeletal muscle. Calcif Tissue Int. 2013 Feb;92(2):151-62.
(20) Nutritional Recommendations for the Management of Sarcopenia. J Am Med Dir Assoc. 2010 Jul;11(6):391-6.
(21) Skeletal muscle myocytes undergo protein loss and reactive oxygen-mediated NF-kappaB activation in response to tumor necrosis factor alpha. FASEB J. 1998 Jul;12(10):871-80.
(22) Implications of cross-talk between tumour necrosis factor and insulin-like growth factor-1 signalling in skeletal muscle. Clin Exp Pharmacol Physiol. 2008 Jul;35(7):846-51.
Austin Baraki is a 25 year old student just a few months away from receiving his M.D. degree. He came to the sport of powerlifting after 15 years of experience competing in and coaching competitive swimming through the collegiate level. Transitioning to powerlifting in the past few years, he has achieved personal best lifts of a 465 lb squat, 355 lb bench press, and a 540 lb deadlift at 5’10” / 185 lbs. He plans to go into the field of Internal Medicine and has a passion for preventive medicine, patient education, lifestyle modification, a nice rare steak, and gainzZz™.