The skeletal muscle accounts for approximately 40% of total body weight [150]. In addition to providing locomotive power, muscle also serves as a reserve of readily available peptides and proteins. Recent progress in sarcopenia research clearly indicates that muscle homeostasis is the result of a precise balance between the anabolic and catabolic processes. A small decrease in synthesis or increase in degradation, if sustained, can lead to a devastating pathological condition. The term sarcopenia was introduced nearly 20 years ago; now, with the worldwide population rapidly aging, this disease is currently gaining more considerable research interest and public attention. Although muscle mass and muscle strength are not always correlated, it is possible that the suppression of muscle protein breakdown is critical for the prevention and treatment of sarcopenia. Understanding detailed mechanisms involved in control of age-related changes in muscle proteins might offer a new therapeutic strategy for patients with sarcopenia.

Omega-3 PUFA supplements might be an effective therapy to prevent or slow down sarcopenia. A number of studies based on rodents and humans have reported enhanced anabolic signaling in skeletal muscle [120]. Studies with C2C12 myotubes or fasted mice have demonstrated that treatment with EPA, but not DHA, significantly increased protein synthesis and decreased protein breakdown [132,144]. Many studies indicate EPA may effectively attenuate the UPS-mediated muscle protein degradation in cachexia murine models [143,144,151]. The mechanism of action mediating NF-κB inhibition appeared to be similar to the antitumor activity of bortezomib on multiple myeloma. Although the effects and mechanistic details of DHA on sarcopenia remain to be further elucidated, our current model suggests that DHA exerts its beneficial effects on muscle atrophy by decreasing proteasomal proteolytic activity by blocking it with oxidized proteins and excess proteasome substrates. However, the results regarding the effectiveness of DHA supplementation in attenuating muscle atrophy in humans are somewhat contradictory. In the RCTs performed by Smith et al., dietary supplementation with omega-3 fatty acids (containing 1.86 g EPA and 1.50 g DHA) significantly increased muscle protein synthesis delays the normal decline in muscle mass and function in older individuals [138,139] while a direct action of EPA and DHA on muscle protein synthesis or degradation was not investigated. Moreover, an 8-week administration of DHA preserved fasting (48 h)-induced muscle atrophy and proteolysis with upregulated autophagy [149]. The concentration, duration, and types of omega-3 PUFAs used in each experiment may directly affect the outcomes. Moreover, cells or organisms may have diverse and sometimes contradictory responses to DHA, which probably depend on the levels of oxidative stress induction.

Growing evidence suggests that the mTOR signaling pathway influences longevity and aging. Inhibition of mTOR signaling with rapamycin (or its derivative rapalogs) is currently the only reliable pharmacological treatment option known to increase longevity in mice, as well as in yeast, worms, and flies, and to prevent age-related conditions in rodents, dogs, nonhuman primates, and humans [152]. mTOR complexes are serine/threonine kinases that lie downstream of Akt in the PI3 kinase pathway and regulate not only protein synthesis but also protein degradation through autophagy [21,153]. Under normal conditions, the free amino acids, the products of proteolysis, stimulate mTOR and facilitate protein synthesis through the downstream effectors, such as ribosomal protein S6 kinase 1 (S6K1) and eukaryotic translation initiation factor 4E binding protein 1 (4EBP1). As rapamycin, rapalogs, and rapamycin metabolites, both endogenous and dietary DHA can target mTOR, altering of downstream effector activation and subsequent protein synthesis [154,155]. However, this also upregulates cellular autophagy (contributing to the anti-inflammaging effects) and subsequently inhibits the UPS, which is more critical for muscle protein degradation. Therefore, the processes involving mTOR probably create a complex crosstalk between the pathways involved in protein synthesis and degradation, although the detailed mechanisms remain to be identified. Dual inhibitory effects of DHA on mTOR signaling and protein catabolism could be a potentially promising strategy to slow aging and extend a healthy lifespan.

Currently, there is no pharmacological intervention method with a clear underlying molecular mechanism to prevent or treat sarcopenia. Considering the increasing recognition of individual and socioeconomic problems associated with sarcopenia, the potential of DHA as an anti-sarcopenic agent should be evaluated more thoroughly through global analysis of cellular oxidative stress and subsequent cellular proteome changes. Relatively newly instituted global standards for the screening and diagnosis of sarcopenia (International Classification of Disease, ICD-10-CM code.M62.84) can be applicable in both prospective and retrospective clinical trials [156]. A small anti-sarcopenic property of DHA would have a big impact on health and quality of life for the older population.