KEY POINTS
- Aging skeletal muscle health is negatively associated with chronic low-grade inflammation, which human and animal studies suggest is at least partially regulated by the cyclooxygenase (COX) pathway.
- Controlling COX-related inflammation may improve the adaptability of aging skeletal muscle to exercise.
- This regulatory information should be integrated into the mosaic of inflammatory control of aging skeletal muscle health and considered in related prevention and treatment strategies.
SYSTEMIC AND TISSUE-SPECIFIC INFLAMMATION
The causes and consequences of inflammation have been of scientific interest since the ancient Greeks built the foundation of modern medicine. Inflammation still can be identified by the four classic signs (rubor, calor, dolor et tumor; redness, heat, pain and swelling) described by Celsus in the first century AD (1,2). Two centuries later, Galen asserted that the inflammatory response was in fact a necessary part of the healing process. In the 1800s, Virchow suggested that loss of function (functio laesa) be acknowledged as the fifth cardinal sign of inflammatory activity within a tissue (1,2). Interest in understanding the role of inflammation in the loss of tissue function paired with technological advancements of the 20th century led to the identification of numerous systemic and tissue-specific inflammatory markers.
Systemic inflammation can be characterized by a large number of inflammatory biomarkers (3–6), and the most common ones include interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP). Severe systemic inflammation occurs in response to various clinical conditions (e.g., sepsis or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection) and is associated with pathologic concentrations of circulating inflammatory markers (7–10). In contrast, chronic low-grade systemic inflammation is characterized by the concentrations of inflammatory markers being only minimally elevated and sometimes is considered a normal part of the aging process (4,11–13). This systemic elevation of proinflammatory markers can then outweigh the influence of anti-inflammatory compounds (14). Collectively, these effects create the net proinflammatory environment that develops with advanced age, otherwise referred to as “inflammaging.” In the 20 years since the term inflammaging was coined by Franceschi et al. (13), research involving the age-associated elevation in inflammation has experienced exponential growth (PubMed citations per year: 2000: 2; 2010: 13; 2015: 63, 2020: 251). As a result, chronic low-grade inflammation has been linked to numerous diseases such as cardiovascular disease, certain cancers, diabetes, certain gastrointestinal diseases, arthritis, dementia, osteoporosis, and sarcopenia (3,4,15).
Tissue-level inflammation is a highly complex and coordinated series of events involving inflammatory and immune cells resident to the tissue and recruited from the vasculature, various membrane-bound and intracellular receptors, and multiple intracellular signaling pathways and compounds (2,16–18). These inflammatory-related events are yet to be fully elucidated and are further complicated by the various instigators of inflammation (e.g., overt tissue injury, acute or chronic exposure to endogenous or exogenous “toxic” compounds). Although the goal is tissue protection and repair, unresolved inflammation can be associated with tissue damage and dysfunction, leading to chronic diseases (2,16–19).
As the underlying cellular pathways that regulate inflammation at the systemic and tissue level are complex and continuing to be unraveled (16–18,20–22), the cyclooxygenase (COX) pathway has emerged as a potential contributor to this process (19,23–27). Several of the prostaglandins produced by the COX pathway are considered to be proinflammatory lipid mediators and have important biological roles in numerous tissues (3,19,23–25,27–29). Much of the insight into the COX pathway has been discovered because of the readily available and commonly consumed COX-inhibiting drugs that are taken acutely and chronically for inflammation and pain (e.g., ibuprofen, naproxen, indomethacin, celecoxib, aspirin, and acetaminophen). The goal of this review is to present the evidence for the association between inflammaging and the decline in skeletal muscle health, and then connect this information to the related COX pathway studies (epidemiological, randomized controlled trials, and preclinical). Collectively, this information provides the basis of the hypothesis that the COX pathway contributes, at least to some degree, to the chronic low-grade inflammation and resultant reduction in skeletal muscle health and plasticity associated with aging. A conceptual schematic of this hypothesis is presented in Figure 1.
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Figure 1: Proposed contribution of the cyclooxygenase (COX) pathway to the effect of inflammation on aging skeletal muscle. The authors hypothesize that the effect of age-related inflammation (i.e., “inflammaging”) on the development of sarcopenia can be mitigated by reducing the contribution of the COX pathway in aging skeletal muscle. Similarly, it seems the influence of age-related inflammation on limiting exercise adaptations can be mitigated by reducing the contribution of the COX pathway, ultimately promoting greater improvements in skeletal muscle health.
AGING, INFLAMMATION, AND SKELETAL MUSCLE HEALTH
It is well established, through several large cohort studies, that aging is associated with increases in circulating inflammatory markers, which in turn are associated with alterations in skeletal muscle mass and function and overall mobility. The Established Populations for Epidemiologic Studies of the Elderly (EPESE; n = 1727) project reported in the late 1990s that circulating IL-6 increased with age in individuals older than 70 yr, and higher levels of IL-6 were correlated with higher levels of functional disability (30). This project also showed that higher levels of circulating IL-6 predicted future onset of disability in older individuals (n = 633) (31). Since these initial reports, several other studies have replicated and extended these findings. The Women’s Health and Aging Study (WHAS; n = 620) showed that the severity of functional disability increased along with IL-6 concentrations and further connected this trend to declining muscle strength (32). The Health, Aging, and Body Composition (Health ABC; n = 3075) study, using computed tomography measures of thigh muscle cross-sectional area and dual-energy x-ray absorptiometry measures of appendicular muscle mass, showed that higher levels of inflammatory markers (IL-6 and TNF-α) were associated with smaller muscle mass, along with lower knee extensor and handgrip strength (33). In a longitudinal follow-up, Health ABC (n = 2177) investigators also reported inflammation-associated declines in thigh muscle size and knee extensor strength through 5 yr (34). The Aging in the Chianti Area (InCHIANTI; n = 1020) study found that circulating IL-6 and CRP levels were negatively correlated with overall physical performance (walking speed, chair stands, balance, handgrip strength) (35). The Longitudinal Aging Study Amsterdam (LASA; n = 986), following older individuals through 3 yr, reported that higher levels of circulating IL-6 and CRP were associated with a two to threefold greater risk of losing greater than 40% of muscle (handgrip) strength over this time period (15).
These larger aging cohort findings have received experimental support from smaller investigations. Lavin et al. (22) and Mikkelsen et al. (36) have reported strong negative associations between magnetic resonance imaging-determined muscle mass and circulating IL-6 and CRP, respectively, across young and older physically active and inactive individuals. These studies also support the notion that physical activity plays an important role in the regulation of the age-associated increase in inflammation and decline in muscle mass. Higher circulating inflammatory status has been shown to be associated with an impaired ability to respond to an exercise training intervention (e.g., increase muscle mass or improve muscle function) in hospitalized geriatric patients (37), mobility-limited older adults (38), older women with knee osteoarthritis (39), and frail and prefrail older adults (40). In support of these outcomes, myocellular studies have shown that an increased susceptibility to proinflammatory signaling likely is linked to reduced skeletal muscle regenerative capacity in older individuals (20).
THE CYCLOOXYGENASE PATHWAY AND SKELETAL MUSCLE HEALTH
Although the underpinnings of the inflammatory regulation of aging skeletal muscle health are complex and multifactorial, the COX pathway in skeletal muscle seems to play a role. Support for this is outlined further in this review and summarized in Figure 2. The substrate for the COX pathway is the cell membrane-derived lipid arachidonic acid, which funnels through the one of two main isoforms of COX (i.e., COX-1 or COX-2) and then through prostaglandin-specific synthases to produce one of several prostaglandins (PGE2, PGF2α, PGD2, and PGI2) (23,25,41). Each of these prostaglandins has one or more specific receptors that regulate downstream cellular events in an autocrine and paracrine fashion (23,25,29,41).
Figure 2: Overview of the PGE2 portion of the cyclooxygenase (COX) pathway (i.e., the PGE2/COX pathway) in skeletal muscle and the proposed series of reactions and downstream regulatory events that influence skeletal muscle mass. Aging and muscle fiber type alter the level of COX pathway components. See text for the studies and specific references that have delineated the items outlined in this schematic. PLA2, phospholipase A2.
One of the key connections between the COX pathway, inflammatory regulation, and muscle mass can be traced through the connection to IL-6. The most abundant PG produced by the COX pathway in skeletal muscle is PGE2 (25) and when human skeletal muscle is incubated with PGE2, it stimulates transcription of IL-6 (42). Interestingly, this same effect has been shown in bone and nerve cells, along with delineation of the receptors and signaling pathways linked to IL-6 promotor activation in those tissues (43–46). Van Hall et al. (47) showed that infusion of IL-6 in healthy volunteers resulted in a 50% reduction in skeletal muscle protein turnover due to protein synthesis being blunted more than protein breakdown, which resulted in net amino acid loss from the muscle. These authors speculated this response was linked to an IL-6–directed increase in amino acid demand in other tissues (e.g., splanchnic tissues) and an associated systemic hypoaminoacidemia. Toth et al. (48) have shown a significant negative relationship between circulating IL-6 concentrations and skeletal muscle protein synthesis rates in young and old men and women. In addition, low level IL-6 infusion into the skeletal muscle of rats induced muscle atrophy (49) and reduced muscle growth (50). It also is noteworthy that PGE2 upregulates skeletal muscle transcription of ubiquitin ligase muscle RING finger-1 (MuRF-1), a central mediator of muscle proteolysis (42,51,52).
Larger observational study findings provide insight into the potential effects of COX inhibition on aging skeletal muscle health. Landi et al. (53), using the Aging and Longevity in the Sirente geographic area (ilSIRENTE; n = 354) study cohort, have investigated the impact of regular consumption of COX-inhibiting anti-inflammatory drugs on sarcopenia incidence in community-dwelling individuals aged 80 yr and older. Using the European Working Group on Sarcopenia in Older People criteria for sarcopenia, 29% of the cohort was diagnosed with sarcopenia, defined as having low physical function and low muscle mass. Individuals were considered COX-inhibiting drug consumers if they took a COX inhibitor (celecoxib, diclofenac, indomethacin, ketoprofen, ketorolac, nimesulide, piroxicam, rofecoxib) at least 5 d·wk−1 during the study observation period, implying they were chronic consumers. These authors showed there was an inverse association between COX-inhibiting drug use and sarcopenia. Sarcopenia was present in only 9% of the drug-consuming group and 31% of the nondrug-consuming group (P < 0.05). Overall, they reported an approximately 80% reduction in risk of sarcopenia with COX inhibitor consumption in this cohort.
Controlling inflammatory burden through COX pathway inhibition also seems to impact the skeletal muscle health benefits derived by older individuals from resistance exercise. In a randomized controlled trial including a 3-month resistance exercise training period, older individuals consuming a COX inhibitor (ibuprofen or acetaminophen) experienced significantly greater improvements in quadriceps muscle mass and muscle strength compared with the placebo-consuming group (54). Follow-up analysis on muscle samples from these trained individuals and separate investigations revealed some cellular explanations for the beneficial effects of COX inhibition (25,42,55–57). Intramuscular transcripts for IL-6 and MuRF-1 were elevated in response to exercise training in the placebo group but were unchanged in the COX inhibitor groups (55). This response likely is due to the COX inhibitor reduction in intramuscular production of PGE2 (25,58), which in turn has been shown to upregulate IL-6 and MuRF-1 transcription in human skeletal muscle (42). Both of these key muscle regulators have been shown to have negative downstream effects on muscle protein turnover and growth (25,42,47,49–52), as discussed previously in this review, which could explain the additional muscle hypertrophy in the COX inhibitor-consuming groups.
In terms of myofiber growth in the trained individuals, additional follow-up analysis demonstrated the placebo group experienced hypertrophy of only the Type II muscle fibers (+26%), whereas COX inhibition resulted in hypertrophy of both Type I (+28%) and Type II (+37%) muscle fibers (54,56). This additional hypertrophy of the Type I fibers in the COX inhibitor group corresponded to increases in phenotypic markers commonly more abundant with this fiber type (the mitochondrial enzyme citrate synthase and capillarization), which were not observed in the placebo group. These fiber type-specific hypertrophy differences between the placebo and COX inhibitor groups also correspond with findings that human Type I muscle fibers (vs Type II) have higher levels of the COX enzyme (COX-1) and PGE2 synthase (mPGES-2), both of which would support higher levels of PGE2 production in Type I muscle fibers (57). Higher levels of PGE2 production could lead to increased PGE2-directed transcription of IL-6 and MuRF-1 in these same Type I fibers (42). In addition, human Type I muscle fibers (vs Type II) have been shown to have higher levels of the proinflammatory PGE2 receptors (EP3) and lower levels of the anti-inflammatory PGE2 receptor (EP4) (22,29,57). Overall, these findings provide insight into the mechanism of the COX inhibitor benefits on myofiber and whole muscle size, and ultimately on muscle function.
There also is support for these human COX inhibitor findings from preclinical studies. Rieu et al. (59) showed 5 months of COX inhibitor treatment in old rats with low-grade inflammation had significant improvements in circulating inflammatory biomarkers, including a 60% reduction in IL-6. COX inhibition also improved albumin synthesis rate and blunted the decline in circulating albumin levels. In addition, in response to feeding, muscle protein synthesis was increased and muscle proteolysis was reduced. These improvements in circulating inflammatory status and muscle protein turnover with chronic COX inhibition translated into increased muscle mass, measured in several muscles of varying fiber type.
The aforementioned effects of COX-inhibiting drugs on skeletal muscle health and adaptations may be specific to older individuals. Skeletal muscle protein synthesis, satellite cell activity, intramuscular signaling, and growth have been shown to be negatively impacted by COX-inhibiting drug consumption in younger individuals (60–65), although negative effects are not universally reported (66–69). The basis for these age-related differences have not been delineated, but may be related to differences in metabolic and molecular control of skeletal muscle adaptations between young and old individuals. To this end, aging alters the level of some components of the COX pathway that may contribute to these differences (57). The findings in younger individuals do underscore the involvement of the COX pathway, prostaglandins, and associated mechanisms in the control of skeletal muscle health-related adaptations.
It should be noted that not all studies of aging and COX inhibition report an influence on skeletal muscle health (70–77). One apparent explanation is related to the dose of COX inhibitor used in some of these investigations. Several studies that have not shown any COX inhibitor influence have examined relatively low doses (ibuprofen: 1.2 g·wk−1 or acetaminophen: 3 g·wk−1) (74–77) compared with those that have shown an influence (ibuprofen: 8.4 g·wk−1 or acetaminophen: 28 g·wk−1) (54–56). For those studies that have used a higher dose and not shown an influence (70,73), specific reasons for the differences across studies are not apparent. Although speculative, the inflammatory burden in the subject population with knee osteoarthritis (73) or the relatively short exercise training program (6 wk) after 2 wk of casting-induced atrophy (70) may have played a role. It also is possible that the COX pathway was not substantially involved in regulating the adaptive responses to exercise in these study populations under the specific study conditions.
SUMMARY
Chronic inflammation often associated with advanced age (i.e., inflammaging) has been identified as a hallmark of numerous chronic diseases, including sarcopenia. As a result, many investigations have attempted to identify the mechanistic underpinnings that drive inflammaging-associated health decline. Chronic inflammation is inherently complex, with many highly integrated response mechanisms, making the existence of a single causative molecular target unlikely. Yet, the COX pathway has emerged as a potential regulator of the health and function of aging skeletal muscle. It is noteworthy that this pathway seems to be involved in the inflammatory-regulated health of several other tissues, which provides indirect support for the proposed hypothesis in skeletal muscle (78–84). Preclinical investigations combined with observations from prospective randomized controlled trials may provide further insight into the complex nature of regulating age-associated COX inhibition in skeletal muscle tissue. Because of potential adverse effects associated with COX-inhibiting drugs, other ways to alter COX pathway activity, either directly or through upstream or downstream mechanistic targets, should be explored. Overall, this information could be useful for the development of guidelines for the prevention and treatment of sarcopenia, with the goal of helping older individuals maintain a healthy, independent lifestyle later in life.
Acknowledgments
This review was based, in part, on work supported by NIH grants AG020532, AG00831, and AG038576.
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