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Thoughts at large: Controversies in clinical nutrition and functional medicine: Issue #5 clinically important considerations concerning loss of muscle mass in chronically ill patients.

1. IS OPTIMAL MUSCLE HEALTH THE KEY TO OPTIMAL BONE HEALTH?

As we all know, for the last several decades our society has placed heavy focus on bone health in the elderly because of its major impact on both quality of life and mortality. However, as we all also know, this focus on bone health, while effective in improving overall health and function in the elderly, has certainly not totally resolved the very common problem of bone loss during aging. Could this lack of optimal success be related to a concept that we learned in basic science classes that did not receive the attention it deserved as we moved from our basic science classes to clinical practice? What is this concept? The skeletal system does not work alone. In contrast, we were all taught about the "musculoskeletal" system.

As we learned when we studied the musculoskeletal system, neither muscle nor bone function in isolation. Rather, they work together in an intricate and harmonious fashion where it is almost impossible for one to function optimally without optimal function from the other. With this basic science dictum in mind, would it not make sense that our efforts to deal with bone loss issues in aging are going to have limited benefit as long as our focus is solely on bone health, particularly when our desired endpoint is improvement of quality of life and the reduction of mortality?

OSTEOPOROSIS AND SARCOPENIA: TWO SIDES OF THE SAME COIN?

More and more researchers are now suggesting that, while efforts to treat bone in isolation may yield improved bone scans, they may yield less than desired clinical benefit in terms of morbidity and mortality unless loss of muscle mass (sarcopenia) is concurrently addressed. In support of this dualistic approach to bone health and function, Matthews et al published the paper "Translational musculoskeletal science: Is sarcopenia the next clinical target after osteoporosis?" (Matthews GDK et al, Ann NY Acad Sci, Vol. 1237, pp. 95-105, 2011). The authors begin their paper by stating what we all know:

"Frailty is a major cause of mortality and morbidity, particularly from falls leading to fracture. One successful intervention for reducing morbidity and mortality from fractures has been the treatment of osteoporosis. "

However, as I have been suggesting, to obtain optimal results we need to go beyond the common clinical practice of focusing solely on osteoporosis:

"While the treatment of osteoporosis is an effective way of reducing the risk of fractures following a fall, it is equally important to reduce the incidence of the falls themselves. The major biological contributor to falls is muscle weakness, frequently attributed to the loss of muscle mass and function, known as sarcopenia. Skeletal muscle has a close functional relationship with bone. Both show major changes during aging and in the same way, sarcopenia and osteoporosis both contribute to frailty."

Next, Matthews et al provide their definition of sarcopenia:

"Sarcopenia refers to the skeletal muscle atrophy and weakness that often accompanies aging. It is a major musculoskeletal cause of loss of mobility, independence, and frailty in older adults. It typically appears as a decrease in muscle mass and more recently has been associated with decreased muscle quality, just as osteoporosis is typified by both decreased bone mass and structural integrity."

Furthermore:

"In common with osteoporosis of bone, it can result from a wide range of factors that include altered central and peripheral nervous system innervation leading to loss of a-motor neurons, hormonal changes, inflammatory effects, and altered caloric and protein intake."

Next, the authors touch upon gender issues. As we all know, osteoporosis has traditionally been considered to be more of a clinical concern in females. This may not necessarily be true with sarcopenia:

"In contrast to osteoporotic change, males and females suffer similar relative losses. Males begin with a higher baseline and so show greater absolute as opposed to proportional losses. Nevertheless, sarcopenia may be a greater public health concern for women, owing to their longer life expectancies, and their increased presentation of higher disability rates."

As I hope you can see, the overall tone of the Matthews et al paper is that bone and muscle health must be addressed in a complementary fashion with equal focus on each if we are truly going to make an impact on concerns of frailty in the elderly. The conclusion of this fascinating paper makes the position of the authors very clear that we need to transform our sometimes "tunnel vision" type of focus on bone health to a type of focus that gives muscle and bone health equal priority:

"Sarcopenia and osteoporosis are both major contributors to the frailty syndrome, an age-related loss of physiological function. Frailty leads to falls, which result in major mortality and morbidity, loss of dignity and confidence, and contribute to other leading causes of death in the elderly, such as cardiovascular and infective complications due to inactivity. Despite several decades of research, the treatment of sarcopenia remains limited, similar to osteoporosis before the mainstream introduction of bisphosphonates in the 1990s. However, recent consensus over the definition, increased awareness among physicians, and numerous insights from the basic sciences have led to exciting prospects for treatment of sarcopenia. The treatment of frailly must now concentrate on taking the individual components of muscle, bone, cardiovascular, and neuronal dysfunction, and treating them concurrently so that each component synergistically improves the other."

2. CAN CHRONIC INFLAMMATION AND ANABOLIC RESISTANCE OF AGING EXACERBATE SARCOPENIA?

As we all know, many in the functional medicine community maintain that chronic inflammation as well as the obvious issue of aging play an integral role in affecting virtually every aspect of how chronic illness presents both clinically and biochemically. Should focus on these two issues include loss of muscle mass (sarcopenia), given that sarcopenia has traditionally been considered as an issue of optimal protein/amino acid intake and weight-bearing exercise? The following papers I am about to highlight suggest that the answer to this question is in the affirmative. In "Chronic low-grade inflammation and age-related sarcopenia" by Beyer et al (Beyer I et al. Chronic low-grade inflammation and age-related sarcopenia, Curr Opin Clin Nutr Metab Care, Vol. 15, pp. 12-22, 2012) the authors state:

"Aging is accompanied by reduced muscle mass and strength, defined as sarcopenia. Catabolic inflammatory processes will enhance this process, especially at advanced age. Even healthy aging results in slight elevations of circulating proinflammatory mediators, corresponding to a chronic low-grade inflammatory profile (CLIP). Elderly persons presenting pronounced CLIP show lower muscle mass and muscle strength."

Another paper that addresses the relationship between chronic inflammation, aging, and sarcopenia is "Skeletal muscle protein metabolism in the elderly: Interventions to counteract the anabolic resistance of aging" by Breen and Phillips (Breen L& Phillips SM. Nutrition & Metabolism, Vol. 8, No. 68, 2011). The first quote I would like to feature from this paper discusses the relationship between aging and loss of muscle mass:

"Age-related muscle wasting (sarcopenia) is accompanied by a loss of strength which can compromise the functional abilities of the elderly. Muscle proteins are in a dynamic equilibrium between their respective states of synthesis and breakdown. It has been suggested that age-related sarcopenia is due to: I) elevated basal-fasted rates of muscle protein breakdown, II) a reduction in basal muscle protein synthesis (MPS), or III) a combination of the two factors. However, basal rates of muscle protein synthesis and breakdown are unchanged with advancing healthy age. Instead, it appears that the muscles of the elderly are resistant to normally robust anabolic stimuli such as amino acids and resistance exercise."

What might cause this anabolic resistance found with sarcopenia? The authors suggest:

"It is not known what causes anabolic resistance in aging muscle. Two theses are that it could be a consequence of the gradual decline in physical activity or an age-related decline in processes related to inflammation, which can interfere with protein turnover..."

Thus, as I hope you can see, while optimization of protein/amino acid intake and weight-bearing exercise are probably the most important therapeutic issues in addressing sarcopenia, overall efficacy of these approaches can definitely be reduced if efforts to reduce chronic inflammation and account for the special needs due to aging are not also considered.

3. RESEARCH ON THE USE OF PROTEIN/AMINO ACID SUPPLEMENTATION TO OPTIMIZE MUSCLE PROTEIN SYNTHESIS

As I suggested above, protein/amino acid supplementation has and continues to be, along with weight-bearing exercise, the most important modality we have when attempting to either prevent or treat sarcopenia. In the above mentioned paper by Breen and Phillips this relationship is addressed. First, consider this very clinically relevant quote which makes clear that, when considering protein supplementation, both dose and source are important:

"The ingested protein dose and source dictates the amplitude and duration of the rise in essential amino acids (EAA's) in the blood, which, in turn, affects the degree of muscle protein synthesis (MPS)."

Of all the common supplemental protein sources, which is most effective? As you might expect, it is whey:

"...we and others have shown, in the context of resistance exercise in young adults, that whey protein stimulates a greater acute (0-3 h post exercise) rise in MPS compared with dose-matched casein and soy proteins, and is still highly effective at stimulating MPS over 3-5h post-exercise."

Why is whey superior over soy?

"The superior capacity of whey to stimulate MPS over that of soy is not due to differing absorption kinetics but likely to be a mere reflection of the lower leucine content of soy versus whey protein."

What might be the uppermost amount of whey protein supplementation in terms of MPS optimization in the elderly? As suggested above, due to anabolic resistance the elderly need higher doses. Breen and Phillips point out:

"...we show that the basal rate of myofibrillar MPS in the elderly plateaus after the ingestion of 20g of whey protein, containing ~10g of EAA."

In contrast:

"...we show that lowest dose of 10g of whey, containing ~5 g or EAA, did not elicit an anabolic response."

Of course, as you might expect, unlike the elderly, low doses are effective in stimulating MPS in the young:

"...we now have preliminary evidence that MPS increases in young muscles sharply after a meal containing low doses of amino acids (5-20g), and becomes saturated after larger doses (20-40g), whereas in the elderly the muscle protein synthetic response is blunted in response to low doses of amino acids."

What is the key factor that determines this difference between young and elderly muscles? It is the amino acid leucine:

" ...we and others have hypothesized the existence of a leucine 'threshold' that must be surpassed after protein ingestion to stimulate MPS above rest."

The next quote discusses this leucine requirement in more detail:

"We postulate that young muscles are highly sensitive to the anabolic actions of leucine as ~1g of orally ingested leucine seems to be sufficient to stimulate MPS above rest. In contrast, our recent observations indicate that the elderly are less sensitive to the anabolic actions of leucine as ~2g of leucine found in 20g of whey protein was required to increase MPS rates above rest."

Therefore, when considering protein supplementation for any patient in whom you desire to increase muscle mass, probably the number one factor to determine about the source of the protein is the leucine content:

"Thus, we suggest that the greater leucinemia associated with rapidly digested high leucine-content proteins may be crucial in order to facilitate a robust muscle protein synthetic response in the elderly."

Other research discussed by Breen and Phillips support the contention that optimal leucine content is critical in optimizing MPS:

"Consistent with the thesis that leucinemia is important in 'driving' MPS, the work of Katsanos and colleagues demonstrated that 6.7g of EAA (equivalent to ~15g of whey), increased MPS above rest in the elderly, but only after the leucine content of EAA s was increased from 26 to 41% (1,7 to 2.8 g)."

The authors continue:

"In line with our hypothesis that younger muscles are more anabolically sensitive, the 26% low-leucine treatment in this study was sufficient to increase MPS in the young. Thus, when considering protein feeding strategies that will acutely increase MPS in the elderly, a protein source with high leucine content and rapid digestion kinetics, in order to promote a transient leucinemia 'spike' would be an effective option."

From a patient management standpoint, what is the best way to supplement protein in the elderly to assure leucine 'spikes'? Breen and Phillips state:

"...older adults should distribute their daily protein equally across three or daily meals. For example, given our findings that the elderly require more protein to increase MPS above rest than the young, in a 75kg individual consuming ~60g or protein daily (based on the RDA of 0.8g/kg-1), this would mean consuming ~20g of protein with each meal, as opposed to a typical feeding regimen in which the elderly typically ingest smaller amounts of protein with breakfast (~8g) and lunch (~12g) and the majority of dietary protein with dinner (~40g)."

Before continuing, I would like to point out that ingestion of RDA levels of protein by the elderly as stated above (0.8g/kg/day) should be considered the minimum amount needed to optimize MPS. In contrast, many authors are now suggesting daily protein intake levels of 1.2-1.5g/kg/day for those elderly patients who wish optimize MPS. Of course, as I mentioned above, resistance exercise is just as important as optimal protein intake in terms of optimizing MPS. Breen and Phillips state:

"Thus, there can be little doubt that utilizing amino acid or protein feeding and resistance exercise concurrently will promote an optimal anabolic environment in elderly muscles compared with either stimulus alone."

How might this concurrent application appear clinically? "It appears that protein ingestion at doses of at least 20g and perhaps as high as 30-40g, in close proximity to, and at intervals over 24 h after resistance exercise, may be able to elicit an anabolic response in the elderly."

SOME FINAL THOUGHTS

While many in the functional medicine community understand the general concept that optimization of muscle mass is important when addressing the needs of chronically ill patients, the clinical specifics of implementation of this concept may not be fully appreciated. Therefore, in summary, please note the following:

* It is highly unlikely that efforts to improve bone health and density will be fully realized without considerations of the need to optimize muscle mass and function also.

* As with virtually every other aspect of chronic illness, chronic inflammation can have a detrimental impact on muscle mass and function and should be considered with any muscle optimization program.

* With aging comes "anabolic resistance" a comparative lack of the ability to improve muscle mass and function with any given intervention compared to what would be seen with younger populations. In turn, muscle building programs employed with the elderly will require higher levels of protein powder and the branched chain amino acid leucine.

by: Jeffrey Moss, DDS, CNS, DACBN
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Author:Moss, Jeffrey
Publication:Original Internist
Date:Sep 1, 2017
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