The Influence of Omega-3 Fatty Acids on Skeletal Muscle Protein Turnover

Omega-3 polyunsaturated fatty acids are proposed to have a range of beneficial effects on human health such as improved immune profile, enhanced cognition, blood lipid regulation, and optimized neuromuscular function⁽¹⁾.  

There is a shift in the omega-3:omega-6 fatty acid ratio in cell membranes that have been demonstrated to induce changes in a variety of biological processes including the expression of pro- and anti-inflammatory lipid mediators and cytokines, gene expression and mitochondrial respiration kinetics⁽²⁾.  

The dysregulation of these processes is linked with impaired metabolic health and omega-3 fatty acid intake could be deemed a viable strategy to combat metabolic dysfunction in a multitude of settings.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the most widely studied omega-3 fatty acids and are found in oily fish and many dietary supplements. EPA and DHA are necessary substrates for the production of anti-inflammatory and inflammation resolving mediators while inhibiting the transcription of pro-inflammatory genes⁽¹⁾.  

The current population recommendations for EPA and DHA intake for general health are typically 250-500 mg/day as a combination of both fatty acids⁽³⁾.

Although humans can synthesize EPA and DHA from dietary alpha linolenic acid, it is very limited. Therefore, dietary, or supplemental intake of preformed EPA and DHA intake is necessary to significantly enhance the EPA and DHA content of biological tissues in humans⁽⁴⁾.
 
Recent evidence indicates a positive influence of EPA and DHA consumption on skeletal muscle. 

This is important because skeletal muscle mass and strength are important in promoting metabolic health and longevity and are critical determinants of recovery from situations of accelerated muscle loss (e.g., surgery/intensive care)⁽⁵⁾.  

This article will examine the data related to the interaction between omega-3 fatty acid ingestion and skeletal muscle anabolism with emphasis on muscle protein turnover.

Skeletal muscle is an extremely important organ, and the loss of skeletal muscle can have dire consequences on our health and quality of life. Understanding the factors that regulate skeletal muscle mass is critical for the development of strategies to support optimal health across the lifespan. 

The size and composition of skeletal muscle is determined by changes in rates of muscle protein synthesis (MPS) relative to those of muscle protein breakdown. There is a transient increase in the rate of MPS which occurs from consuming high-quality protein rich in essential amino acids. This results in a positive state of muscle protein balance.

In addition, resistance exercise increases MPS which stays elevated about 48 hours post-exercise. Thus, protein feeding and resistance exercise convey additive effects on MPS and net protein balance⁽⁶⁾ so when repeated sessions of resistance exercise are combined with adequate protein feeding there is a prolonged state of positive muscle protein balance leading to a gradual increase in skeletal muscle size⁽⁷⁾.

Omega 3 Fatty Acids and Muscle Protein Turnover

In an animal model, omega-3 fatty acid supplementation increased the omega-3 fatty acid composition of skeletal muscle membrane phospholipids that coincided with enhanced phosphorylation of mechanistic target of rapamycin (mTOR) and ribosomal protein of 70 kDa S6 (p70S6K1), two key proteins known to regulate skeletal MPS⁽⁸⁾.  

In addition, human studies indicate that omega-3 fatty acid consumption increased the omega-3 fatty acid composition of skeletal muscle phospholipids that is linked to enhanced rates of mixed MPS supporting gains in skeletal muscle mass and size over time⁽⁹⁾.

It’s important to note that the age-related loss of skeletal muscle mass and strength with advancing age (called sarcopenia), is now recognized as an independent condition (International Classification of Disease, ICD-10-CM), the use of omega-3 fatty acids to promote skeletal muscle anabolism may soon prove to have important efficacy in geriatric populations.

Counteracting Skeletal Muscle Loss with Omega-3 Fatty Acids

Given that omega-3 fatty acid supplementation enhances amino acid and insulin-mediated increases in rates of MPS^{(16, 17)}, it is possible that omega-3 fatty acid intake may serve to attenuate disuse-induced declines in MPS and thus attenuate muscle loss. Recent evidence demonstrated that 6 weeks of ~3g/day EPA and ~2g/day DHA attenuated declines in muscle volume and muscle mass during 2-weeks of unilateral leg immobilization in young women⁽¹⁰⁾.  

Although positive results were seen in young women, it is unknown whether omega-3 fatty acid feeding protects muscle loss during periods of muscle-disuse in older men and women or younger men. Further work in these populations and in situations that mimic real-life clinical scenarios of muscle-disuse would add to these findings.

As omega-3 fatty acid intake has been shown to confer anabolic influence in ostensibly healthy individuals, it is entirely possible that omega-3 fatty acid intake may also positively impact skeletal muscle in situations of disease.

Figure: (A) Time course change in skeletal muscle lipid content with omega-3 fatty acid supplementation. (B) Potential clinical scenarios for the use of omega-3 fatty acid supplementation to promote and/or mitigate losses in skeletal muscle mass; eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), muscle protein synthesis (MPS), muscle protein breakdown (MPB)⁽²⁾

Mechanisms of Action of Omega-3 Fatty Acids

Traditional thought is that their anti-inflammatory properties are primarily responsible for many of the reported health benefits of omega-3 fatty acids. In diseased states that often come with a state of excessive inflammation, the production of anti-inflammatory molecules and corresponding suppression of pro–inflammatory agents induced by omega-3 fatty acids is thought to support improved health status⁽¹⁾.  

However, in healthy adults, consumption of omega-3 fatty acid enhanced MPS and muscle mass⁽¹⁸⁾ in the absence of any corresponding change in the concentration of supposed circulating inflammatory markers. These findings indicate that in non-pathological states, omega-3 fatty acids do not confer anabolic influence via an anti-inflammatory mechanism.  

The potential actions of omega-3 fatty acids in skeletal muscle are illustrated by the schematic below.

Figure: Schematic illustration of molecular mechanisms of action of omega-3 fatty acids in skeletal muscle. 1. Translocation of the mechanistic target of rapamycin complex-1 (mTORC-1) with the lysosome to the membrane in close proximity to amino acid transporters. 2. Enhanced adenosine diphosphate (ADP) sensitivity and altered reactive oxygen species emissions (ROS). 3. G-coupled protein receptor 120 (GPR120) and free docosahexaenoic acid (DHA)-mediated production of resolvins, protectins, and maresins. 4. Cystolic retention of nuclear factor kappa B (NF-κB) preventing upregulation of proteolytic and pro-inflammatory agents. 5. Altered lipid raft formation that acts as signaling platforms for unknown signaling agents; eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA)⁽²⁾

EPA vs. DHA

Whilst studies often provide EPA and DHA in combination, both fatty acids are known to exert independent biological actions. Evidence indicates that EPA may have a greater influence on muscle protein turnover⁽¹¹⁾ whereas DHA, likely due to its higher content in neuromuscular tissues [~50 times higher than EPA in brain], is heavily involved in neuromuscular function⁽¹²⁾.

There are no studies directly comparing the effect of physiological doses of EPA vs. DHA ingestion on rates of MPS or protein breakdown in humans. Given that EPA and DHA serve as the substrates to produce different pro-and anti-inflammatory mediators (e.g., resolvins) each with their own specialized function⁽¹⁾, defining the mechanisms behind how EPA and DHA modify muscle protein turnover in an in vivo setting is an exciting area worthy of future work.

Mitochondrial Function

Besides the sarcolemma, mitochondrial membranes are known to be sensitive to omega-3 fatty acid intake. Research indicates that increasing mitochondrial content of EPA and DHA is concordant with enhanced ADP sensitivity⁽¹³⁾.  

This is important because ADP insensitivity impairs mitochondrial function in aging muscle including reports of decreased ATP production and increased reactive oxygen species⁽¹⁴⁾.  

There is evidence that omega-3 fatty acid-mediated changes in mitochondrial function may play a role in mitigating muscle loss during aging and periods of muscle disuse. Enhanced ADP sensitivity is also important as ADP-stimulated oxidative phosphorylation decreased reactive oxygen species emission, and aberrant reactive oxygen species have been implicated in the pathology of muscle-disuse atrophy⁽¹⁵⁾.  

Collectively, research indicates that the protection of mitochondrial function plays a key role in the regulation of muscle size during periods of muscle-disuse in young women, which may be alleviated by omega-3 fatty acid supplementation⁽²⁾.

Anti-inflammatory Effects of Omega-3 Fatty Acids

Inflammatory markers (e.g., CRP, IL-1, IL-6, and TNF) associated with disease states such as cancer cachexia are known to trigger regulators of proteolysis that in turn promote muscle loss⁽¹⁶⁾.  

The classic mechanism of action by which EPA and DHA alter the production of pro-inflammatory cytokines is through modification in the synthesis of lipid mediators, mainly derivatives of the omega-6 fatty acid arachidonic acid (ARA) and of EPA and DHA themselves. These lipid mediators are biologically active and include prostaglandins and leukotrienes as well as specialized pro-resolution mediators.

The effects of EPA and DHA on production of prostaglandins and leukotrienes and on pathways that reduce NF-κB (transcription factor that acts to up-regulate inflammatory gene expression) activation and subsequent production of pro-inflammatory cytokines, chemokines and adhesion molecules are generally regarded as being anti-inflammatory⁽¹⁾.  

It’s well established that EPA and DHA are substrates for lipid mediators that actively turn-off inflammation(17). 

Summary

Available evidence to date indicates that omega-3 fatty acid intake has the potential to enhance skeletal muscle anabolism, but the size of the effect may be contingent upon several variables. These variables include, but are not limited to, the daily dose of protein intake, measurement technique utilized in the study, as well as age and metabolic status of participants.

A particularly promising area is the potential for omega-3 fatty acids to counteract muscle atrophy and promote recovery from periods of muscle-disuse.

However, before firm conclusions can be made on omega-3’s efficacy on musculoskeletal health and subsequent translation to the clinical setting there remains many unanswered questions that require experimental attention.

Future work in this area will provide crucial information for the development of omega-3 fatty acid therapies to promote musculoskeletal health in a variety of populations and settings.

Omega-3's EPA and DHA have long been shown to have positive effects on the brain.

EPA and DHA are almost exclusively found in fatty fish, but because many people do not consume the recommended amounts of fish on a weekly basis, fish oil supplements are a simple way to fill the gaps. You can learn more about the effects of fish oil on brain health here.  



References:
    1.    Calder PC: Omega-3 fatty acids and inflammatory processes: from molecules to man. Biochem Soc Trans 45:1105-1115, 2017
    2.    McGlory C, Calder PC, Nunes EA: The Influence of Omega-3 Fatty Acids on Skeletal Muscle Protein Turnover in Health, Disuse, and Disease. Front Nutr 6:144, 2019
    3.    Thompson M, Hein N, Hanson C, et al: Omega-3 Fatty Acid Intake by Age, Gender, and Pregnancy Status in the United States: National Health and Nutrition Examination Survey 2003(-)2014. Nutrients 11, 2019
    4.    Nording ML, Yang J, Georgi K, et al: Individual variation in lipidomic profiles of healthy subjects in response to omega-3 Fatty acids. PLoS One 8:e76575, 2013
    5.    Wischmeyer PE, Puthucheary Z, San Millan I, et al: Muscle mass and physical recovery in ICU: innovations for targeting of nutrition and exercise. Curr Opin Crit Care 23:269-278, 2017
    6.    Witard OC, Tieland M, Beelen M, et al: Resistance exercise increases postprandial muscle protein synthesis in humans. Med Sci Sports Exerc 41:144-54, 2009
    7.    Morton RW, Murphy KT, McKellar SR, et al: A systematic review, meta-analysis and meta-regression of the effect of protein supplementation on resistance training-induced gains in muscle mass and strength in healthy adults. Br J Sports Med 52:376-384, 2018
    8.    Dickinson JM, Fry CS, Drummond MJ, et al: Mammalian target of rapamycin complex 1 activation is required for the stimulation of human skeletal muscle protein synthesis by essential amino acids. J Nutr 141:856-62, 2011
    9.    Smith GI, Julliand S, Reeds DN, et al: Fish oil-derived n-3 PUFA therapy increases muscle mass and function in healthy older adults. Am J Clin Nutr 102:115-22, 2015
    10.    McGlory C, Gorissen SHM, Kamal M, et al: Omega-3 fatty acid supplementation attenuates skeletal muscle disuse atrophy during two weeks of unilateral leg immobilization in healthy young women. FASEB J 33:4586-4597, 2019
    11.    Jeromson S, Mackenzie I, Doherty MK, et al: Lipid remodeling and an altered membrane-associated proteome may drive the differential effects of EPA and DHA treatment on skeletal muscle glucose uptake and protein accretion. Am J Physiol Endocrinol Metab 314:E605-E619, 2018
    12.    Salem N, Jr., Litman B, Kim HY, et al: Mechanisms of action of docosahexaenoic acid in the nervous system. Lipids 36:945-59, 2001
    13.    Herbst EA, Paglialunga S, Gerling C, et al: Omega-3 supplementation alters mitochondrial membrane composition and respiration kinetics in human skeletal muscle. J Physiol 592:1341-52, 2014
    14.    Pharaoh G, Brown J, Ranjit R, et al: Reduced adenosine diphosphate sensitivity in skeletal muscle mitochondria increases reactive oxygen species production in mouse models of aging and oxidative stress but not denervation. JCSM Rapid Commun 4:75-89, 2021
    15.    Powers SK, Smuder AJ, Criswell DS: Mechanistic links between oxidative stress and disuse muscle atrophy. Antioxid Redox Signal 15:2519-28, 2011
    16.    Crossland H, Skirrow S, Puthucheary ZA, et al: The impact of immobilisation and inflammation on the regulation of muscle mass and insulin resistance: different routes to similar end-points. J Physiol 597:1259-1270, 2019
    17.    Serhan CN, Chiang N: Resolution phase lipid mediators of inflammation: agonists of resolution. Curr Opin Pharmacol 13:632-40, 2013

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