By Austin Baraki
- In our first article we defined sarcopenia as a loss of skeletal muscle mass and strength, and discussed how disuse, poor nutrition, neuromuscular changes, hormonal status, and chronic inflammation contribute to loss of skeletal muscle protein.
- In part 2 we explored a few mechanisms that stimulate muscle protein synthesis including resistance exercise, dietary protein (especially leucine), and several hormones/cytokines. We then showed how this process translates into muscle hypertrophy, with consequences for the atrophic/elderly population that proved “it’s never too late!”
- Today we’ll examine a few factors influencing skeletal muscle “quality,” then discuss the clinical diagnosis of sarcopenia and its challenges.
Recall from our prior articles that a decline in skeletal muscle mass is just one criterion for sarcopenia; in addition, there must also be a loss of strength or physical performance (1). This second criterion was added because the relationship between muscle cross-sectional area (i.e. size) and force production (i.e. strength) is much less predictable with aging compared to younger individuals (1,2). In other words, aging results in much more rapid strength and power losses than changes in muscle size alone would predict, suggesting that there are changes in “muscle quality” that occur independently of changes in muscle mass (2,3). It turns out that muscle quality (i.e strength per unit mass) “appears to be a stronger predictor of performance than strength, mass, or body composition alone in older adults” (3). We’ll begin this article by looking at a few factors affecting muscle quality, including neuromuscular changes, structural changes, muscle infiltration, mitochondrial dysfunction, and microvascular dysfunction.
- Neuromuscular changes occur in older/aging muscle, a concept that was first mentioned in part 1 of this article series. We described how aging and disuse result in the loss of motor neurons and their end plates (“electrical outlets”), particularly for fast-twitch muscle fibers (3,4,5,6). In that article we focused on how this process leads to protein breakdown and atrophy of muscle fibers, but we also briefly described the process of collateral re-innervation. This occurs when a denervated (“unplugged”) muscle fiber gets saved by the nerve controlling a neighboring motor unit. Unfortunately, when a FAST-twitch muscle fiber gets re-innervated by the nerve of a SLOW-twitch motor unit, it gets forced to switch fiber types in order to join the group! So these denervated muscle fibers must either transform into slower, weaker slow-twitch fibers, or wither away completely. Neither of these are ideal, but at least one conserves some muscle mass that would otherwise be lost. Unfortunately, though, it still causes a deterioration in muscle quality. The overall shift from fast-to-slow-twitch fiber composition will diminish maximal strength and power production, and the “grouping” process results in very large motor units that are difficult to coordinate, resulting in poor motor control, force steadiness, and balance difficulty. Other neuromuscular changes of aging include deficits in motor unit firing rates, agonist/antagonist co-activation and loss in number and size of large myelinated nerve axons, all of which further reduce maximum force production and neuromuscular efficiency (7,7a).
- Several structural changes occur in aging skeletal muscle that can impair muscle function. Healthy muscle is a remarkably well-organized and orderly tissue down to the sarcomere level (see image below), and disruptions of this arrangement affect efficiency of force production and transmission. Muscle atrophy causes decreases in muscle fiber length, and this shortening coupled with age-related loosening of tendons results in decreases in pennation angles (the directional “line of pull” of muscle fibers) (3,8). Shorter fibers can’t contract with the high velocities needed for power output, and altered pennation angles weaken muscles’ effective leverage against the skeleton (3). Fortunately, muscle hypertrophy results in the opposite adaptations – longer fiber lengths allow greater contraction velocities due by optimizing cross-bridging, and greater pennation angles improve muscular leverages to maximize force (9).
Sarcomere structure and organization is another crucial determinant of muscle contractile function. Electron micrograph studies of older muscle have shown disordered myofibrils, damage (“streaming”) of the sarcomere Z-disks, and abnormal swelling of the sarcoplasmic reticulum, all of which impair contractile function (3,10,11). Furthermore, part of the sarcomere contractile force is transmitted via the extracellular matrix (ECM) “scaffolding” throughout muscle tissue. This ECM also undergoes unfavorable changes in aging, including excessive accumulation of collagen and altered elasticity that impairs efficient force transmission (3,12).
Electron micrograph of human skeletal muscle organized into sarcomeres, divided by Z-disks shown as thick black lines. Source
- Muscle infiltration is yet another mechanism by which muscle quality can decline. As we’ve already discussed, sarcopenia occurs by a variety of mechanisms including disuse, inadequate protein intake, hormonal and inflammatory processes, etc. In addition to atrophy and loss of motor units, these mechanisms can cause skeletal muscle “infiltration” with fat and scar tissue (“fibrosis”) (2,3,12). The fat can deposit between or within muscle cells (extra- vs. intramyocellular lipids), contributing to lipotoxicity, insulin resistance, and impaired muscle function (13). There is also some evidence that this intracellular fat accumulation is an underlying cause of the “anabolic resistance” phenomenon we introduced in part 2 (14). Of course, this fat and scar tissue are useless for force production since they can’t contribute to muscle contraction. In fact, interference by this non-contractile tissue actually impairs muscle function, decreasing strength more than would be expected for the muscle’s total CSA (3,12). In addition, chronic disease conditions including diabetes/metabolic syndrome, HIV, cancers, autoimmune diseases (e.g. rheumatoid arthritis, lupus), muscular dystrophies, and many others can further exacerbate muscle atrophy and fatty/fibrotic infiltration. As an interesting aside: endurance training stimulates a marked increase in muscle fat content (mostly intramyocellular) (13,15). This adaptation provides long-acting energy availability for their muscles during exercise, and it seems plausible that this intramuscular fat might similarly interfere with maximal force and power production, but this remains to be studied and conclusively proven.
- And if what we’ve covered so far isn’t depressing enough, there are two other mechanisms believed to contribute to impaired muscle quality & function that I will mention briefly here. Mitochondrial dysfunction results from the accumulation of mtDNA mutations and oxidative stress (e.g. from obesity, metabolic syndrome and many other conditions) that leave muscle cells unable to generate enough energy for proper function (16,17,18). Microvascular dysfunction (i.e. abnormal blood flow) resulting from aging, obesity, and inactivity all dampen the physiologic capillary reactivity that matches blood flow to muscle oxygen demand (19). While this process is normally mediated by ATP, nitric oxide, insulin, and other vasoactive factors, limiting blood flow to any organ has obvious negative effects on metabolism and function. Arteriosclerosis and membrane thickening also occurs within capillaries, further impairing oxygen delivery to muscle tissue (20). Fortunately for us, Mary Conover’s article article featured on the Starting Strength website covers this topic in more detail, as well as some discussion focused on training elderly clients.
At this point we’ve discussed several mechanisms by which muscle “quality” decreases independently of changes in size, impairing strength and function. Muscle quality appears to be at least as (if not even more) important than total muscle mass in older individuals, particularly when it comes to treating sarcopenia (more on this in part 4 – let’s not get ahead of ourselves).
DIAGNOSIS OF SARCOPENIA
Now that we’ve thoroughly explored our definition of sarcopenia, how do we make the diagnosis in a real person? Although it might be too obvious to miss in some patients, we still need a reproducible, objective diagnostic method. There have been a number of scientific “working groups” (SIG, EWGSOP, IWGS, SCWD, NIH) all looking at this particular issue over the years, but unfortunately we still don’t have an “operational definition” based on a uniform set of clinical diagnostic criteria (21,22). Depending on which criteria are used, estimated prevalence of sarcopenia in community-dwelling people over 60 years old can range from 3-52% (23)! This massive range shows how badly we need a more rigorous diagnostic method. In this section we’ll take a look at the current modalities that have been studied.
A number of techniques have been examined for quantifying skeletal muscle mass (criterion #1). We can measure total skeletal muscle mass and compare to young, healthy controls, or measure just the appendicular (arms/legs) lean mass (ALM), and normalize the value for height or BMI (ALM/height2 or ALM/BMI) (1,22). In choosing among the available measurement techniques, we must consider their accuracy, precision, reproducibility, sensitivity to change over time, and accessibility (7). The 4-Compartment method (4C), CT scanning, and MRI are considered the “gold standard” methods for assessment of skeletal muscle mass (1,2,3,24). CT and MRI can accurately assess cross-sectional areas, volumes, muscle densities and fatty/fibrotic infiltration. However, these methods are very expensive, limited in availability, and CT scanning adds risks of radiation exposure.
Dual X-ray Absorptiometry (DXA or DEXA) scanning is a rapid, inexpensive, and low-radiation scanning modality already used in research and clinical settings (e.g. osteoporosis screening) to distinguish soft tissues and bone (1,2,3,24). DXA has been shown to closely correlate with MRI, CT and 4C measurements, and an added benefit is that it could be used for simultaneous screening of sarcopenia and osteopenia/osteoporosis since many women already get osteoporosis screening at 65 or older. While DXA is a very promising tool, it does have one major weakness: it cannot detect fat infiltration or fibrosis to assess muscle quality (3). This is important given our discussion so far showing why muscle size isn’t everything in older people!
Example DXA scan Source
Skeletal muscle ultrasound is a cheap, widely available, and very promising technique for imaging-based assessments of muscle size and quality (2,3,24). It is an accurate and reliable method to measure muscle CSA, thickness, volume, and it can even provide a look at fatty/fibrotic infiltration by way of echo intensity (3). Interestingly, some evidence shows that hypertrophic changes in muscle may be visualized by ultrasound even before they appear on DXA (3)! This could make serial ultrasound assessments valuable in tracking the response to interventions over time. Of course, this technique is impractical for measuring total muscle mass (we wouldn’t ultrasound every muscle in the body), so perhaps further research could use a few major muscle groups to establish reference values for whole-body correlation, or we could just use it as a tool for quick follow-up evaluations.
A few other techniques have been suggested, but are unlikely to play a major role anytime soon so I’ll only mention them briefly here. Electrical Impedance Myography (not to be confused with Bioimpedance Analysis) is a painless and noninvasive technique based on applying electrical currents to specific muscles (3). It can detect changes in muscle quality due to fatty/fibrotic infiltration and has already been validated in patients with Amyotrophic Lateral Sclerosis (ALS, Lou Gehrig’s disease), and could be a useful adjunct method in the future. Motor Unit Number Index (MUNIX) is a similar technique using rapid surface EMG measurements to estimate the number of motor units in a given muscle (another factor in muscle quality). It has already been validated for long-term use in ALS patients and has also been used in sarcopenia studies (5). In contrast, Bioimpedance Analysis is a popular, simple, and cheap test used to measure body composition, but it is a very unreliable and insensitive test due to the effects of fluid status and other physiologic parameters (24). Although some organizations have suggested it might be useful as a rapid, portable screening tool, it appears to be unnecessary for screening given the other tools we have available, and is not sensitive or accurate enough for diagnostic use either.
Muscle strength (part of criterion #2) is a more straightforward assessment in the clinical setting, and the Handheld Dynamometer device has been shown to be an excellent tool for this purpose (1,2,24). It is an accurate, reliable and inexpensive technique that can measure hand grip, ankle, elbow, hip, and knee strength. Most of the working groups on sarcopenia recommend assessment of hand grip strength, but unfortunately the selected “cutoff” values seem to have wide variation, ranging from 40 and 30 kg for males and females respectively (European Working Group), to 26/18 kg (Asian Working Group) or even 26/16 kg (National Institutes of Health) (22). This variation has considerable implications for who may or may not earn the diagnosis of sarcopenia! Furthermore, it could be argued that lower-body strength is much more important for the older individual to maintain independence and functional activity, and we should focus on that rather than grip strength (24). Unfortunately this has not been studied nearly as much at this point, but there has been one validated formula using a simple sit-to-stand test to assess knee extensor strength (25). One important limitation of any strength assessment is variability in patient effort, which can be influenced by things like depression, pain, or cognitive impairment (2,3).
Several tools have been proposed to assess aspects of muscle function/physical performance (the other part of criterion #2). A basic gait speed measurement is one of the simplest screening tests for sarcopenia, and has been extensively studied and validated. Most scientific working groups on sarcopenia have agreed on cutoff values of 0.8-1.0 m/s for gait speed testing (1,21,22,24). Another excellent clinical tool is the “Short Physical Performance Battery” (SPPB), which includes repeated chair stands, balance testing, and a timed 8-foot walk. Scoring ranges from 0 (worst) to 12 (best), and is predictive of risk for mortality, disability, and nursing home admission. These are simple, inexpensive, and easily assessed parameters in the vast majority of patients.
A more recent proposal of note is the SARC-F questionnaire (although there are many, many others). The SARC-F is a simple 5-item screening questionnaire asking about strength, assistance with walking, rise from a chair, climbing stairs, and falls to generate a composite score from 0-10. The scoring system has shown high sensitivity and predictive power for adverse events, but, being a screening test, is intended for use in older demographics with an already high prevalence of sarcopenia (27). It has been suggested that a composite scoring method taking other risk factors and comorbid diseases (e.g. obesity, cardiovascular, lung, liver, kidney, or autoimmune diseases) into account might be useful as a predictive tool for younger-aged individuals as well, similar to the FRAX tool for osteoporosis and hip fracture risk (22,27).
The SARC-F questionnaire (From sources 26-27). Scores ≥ 4 indicate impaired function requiring further evaluation.
Finally, biomarkers are widely used in medicine for a range of conditions and diagnoses because they can be very useful for screening, diagnosis, and evaluating responses to treatment using simple blood or urine tests (3,7). The number of biomarkers correlated with sarcopenia is quite large and includes inflammatory markers (CRP, IL6, TNFa), hemoglobin, albumin, urinary creatinine, hormones (serum DHEA-S, testosterone, IGF-1, vitamin D), products of oxidative stress/damage, and several others. This long list reflects the large number of mechanisms contributing to sarcopenia, many of which we have covered in these articles. Unfortunately, as you may have already guessed, none of these are specific to muscle and are easily confounded by other comorbid disease processes, making them fairly useless for our needs in diagnosing and monitoring sarcopenia over time. There have been two promising candidates for more specific biomarkers, although they aren’t quite ready for clinical use yet. Plasma levels of Procollagen type 3 N-terminal Peptide (P3NP) serve as a marker of skeletal muscle remodeling; it tends to be decreased in older individuals, and changes in P3NP levels appear to be predictive of changes in muscle mass and strength (3). Another molecule, C-terminal Agrin Fragment (CAF), is a fragment normally released into the serum during neuromuscular remodeling; however, excessive cleavage of the molecule is associated with loss of the neuromuscular junction (which, if you’ll recall from our earlier discussion, is a major contributor to sarcopenia!) (3). With some more research, these molecules may end up being useful to measure in the clinical setting; but until then, we are left without many good options in terms of specific biomarkers for sarcopenia.
Below is the suggested diagnostic algorithm proposed by the European Working Group on Sarcopenia in Older People (EWGSOP) (from source 1). Consider what some of it’s limitations might be before next week’s article.
Let’s wrap this article up. To summarize, we’ve discussed:
- How neuromuscular changes, structural changes, infiltration (fat/fibrosis), mitochondrial dysfunction, and microvascular dysfunction can impair muscle “quality” independently of changes in muscle size.
- The challenges of diagnosing sarcopenia clinically, including practical techniques for measuring muscle mass and quality (DXA, ultrasound), muscle strength (handheld dynamometry), and muscle function/physical performance (gait speed, SPPB, SARC-F).
In the next and final article we’ll tie everything together and discuss practical implications for the most important topic of all, TREATMENT AND PREVENTION of sarcopenia!
Austin Baraki is a 25 year old student just three months away from completing 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. Since transitioning to powerlifting he has achieved personal best lifts of a 480 lb squat, 365 lb bench press, and has deadlifted 525×4 at 5’10”/185 lbs. He is specializing in Internal Medicine and has a passion for coaching, teaching, preventive medicine, a nice rare steak, and making gainzZz™.
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