Myokine Response to Resistance Exercise in Older Adults and the Similarities and Differences to Younger Adults: A Brief Narrative Review
Applied Health Sciences Program, University of Manitoba, Winnipeg, Manitoba, R3T 2N2, Canada
Pan Am Clinic Foundation, 75 Poseidon Bay, Winnipeg, Manitoba, R3M 3E4, Canada
Faculty of Kinesiology and Recreation Management, University of Manitoba, Winnipeg, Manitoba, R3T 2N2, Canada
Centre on Aging, University of Manitoba, Winnipeg, Manitoba, R2T 2N2, Canada
Academic Editors: Wook Song and Calogero Caruso
Special Issue: Musculoskeletal Aging and Sarcopenia in the Elderly
Received: May 30, 2022 | Accepted: September 25, 2022 | Published: October 07, 2022
OBM Geriatrics 2022, Volume 6, Issue 4, doi:10.21926/obm.geriatr.2204206
Recommended citation: Cordingley DM, Cornish SM. Myokine Response to Resistance Exercise in Older Adults and the Similarities and Differences to Younger Adults: A Brief Narrative Review. OBM Geriatrics 2022;6(4):18; doi:10.21926/obm.geriatr.2204206.
© 2022 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.
Sarcopenia refers to the age related loss of muscle mass, strength and performance which are associated with respiratory disease , heart failure , quality of life, health care costs , activities of daily living , and falls and fractures . Exercise, and in particular resistance exercise, is one component suggested for the prevention and treatment of sarcopenia . It has been postulated that myokines may be responsible for improvements in skeletal muscle health in response to exercise in older adults either in an autocrine or paracrine fashion .
Myokines are proteins and polypeptides, of which some are part of the cytokine family, and are secreted from skeletal muscle . Myokines are sometimes referred to as “exerkines” because of their secretion with exercise and are considered as potential modulators of exercise mediated health improvements; however, exerkines can be released from multiple types of tissue [9,10]. Certain myokines are correlated with changes in muscle strength, mass and strength per kg of fat free mass in response to resistance exercise . An individual’s myokine response to exercise may contribute to the benefits of exercise in managing sarcopenia . However, most research to date has investigated the myokine response in older adults to aerobic type exercise (i.e., walking, running, cycling) with fewer studies investigating the response to resistance exercise . Resistance exercise is a potent stimulus for myokine secretion in younger adults ; therefore, the purpose of this review is to outline the response of select myokines to resistance exercise in older adults and compare this response to younger adults.
2.1 Interleukin-6 (IL-6)
Interleukin-6 (IL-6) was one of the first molecules to be proposed as a myokine as it is secreted from skeletal muscle and can exert effects on other biological organs . IL-6 is primarily known for its pro-inflammatory characteristics, however when secreted in response to skeletal muscle contraction it results in anti-inflammatory effects by signaling the release of other anti-inflammatory type cytokines such as IL-1 receptor antagonist and IL-10 . Additionally, aside from being anti-inflammatory, which is likely beneficial for preserving muscle mass in older age, IL-6 is postulated to contribute to muscle hypertrophy in response to resistance exercise training (for review see ). In humans, the acute response of IL-6 to a bout of resistance training has been found to significantly correlate with muscle hypertrophy in response to a resistance training program in young and older men [11,15]. Mechanistically, from an animal model, IL-6 may encourage hypertrophy by stimulating skeletal muscle satellite cell proliferation and myogenic differentiation . Following muscle damage from eccentric skeletal muscle actions in humans, signal transducer and activator of transcription 3 protein (STAT3), within the nuclei of skeletal muscle satellite cells, is induced by IL-6 suggesting satellite cell proliferation . In a cultured myotube model, IL-6 can also signal the stimulation of mammalian target of rapamycin complex 1 (mTORC1), which is one of the main mechanisms driving protein synthesis in skeletal muscle . Although the data is limited, the response of IL-6 to a bout of resistance exercise is similar between younger and older males regardless of the training status (i.e., untrained or trained) of the individual [11,19].
Particularly important with aging is the ability of resistance training to be anti-inflammatory which could help slow muscle atrophy. With progressing age a human experiences numerous stressors, which in combination with genetics and the environment often results in an increased pro-inflammatory state known as “inflammaging” . In a group of 986 older men and women (mean age ± SD: 74.6 ± 6.2 yrs) it was found that higher levels of IL-6 were associated with a 2 to 3-fold greater risk of muscle strength losses over a 3-year period . A study investigating an 8-week resistance training program in obese (41.0 ± 6.2% body fat) older women (age, 68.2 ± 4.2 yrs) found that a whole body resistance training program performed 3-days per week resulted in decreased resting IL-6 compared to the control group . Interestingly, high amounts of adipose tissue, as found in overweight/obesity, are associated with a pro-inflammatory state which includes high concentrations of circulating IL-6; however, aerobic exercise training, at least in a murine model, is able to promote increased lipolysis in visceral adipose tissue via activation of the lipolytic pathway by skeletal muscle derived IL-6 . Although adipose tissue can produce high levels of IL-6, it has been suggested it is the secretion of tumour necrosis factor-alpha (TNF-α) which can stimulate the release of IL-6 from adipose tissue. In this case, TNF-α is the pro-inflammatory cytokine which induces metabolic disease and likely drives the increase in IL-6 . Also, it may be different isoforms of IL-6 are released from muscle, adipose tissue, or inflammatory cells and these isoforms have various roles to play physiologically or pathophysiologically . It is proposed that physical activity can play an important role in promoting longevity , with current evidence suggesting the response of IL-6 to acute and chronic exercise being one possible mechanism of action to reduce chronic inflammation via stimulation of anti-inflammatory cytokines such as IL-10 and IL-1 receptor antagonist.
Myostatin is a member of the transforming growth factor beta (TGF-β) super family and down regulates muscle growth . In a murine model, inhibition of myostatin gene expression results in individual muscles with a 2-3 times greater mass than in wild-type animals . Insulin-like growth factor 1 (IGF-1) activity is antagonized by myostatin on the protein kinase B (Akt) pathway . Myostatin signaling inhibits the activation of the Akt/mammalian target of rapamyacin (mTOR)/p70S6k pathway resulting in decreased myoblast differentiation and myotube hypertrophy , and decreased protein synthesis . In a murine model of resistance exercise, myostatin signaling was decreased by the activation of the TGF-β inhibitor termed Notch which resulted in a decrease in transcriptional activity of myostatin and increased hypertrophy . Thus, resistance exercise results in myostatin inhibition .
One study has compared myostatin messenger ribonucleic acid (mRNA) expression from muscle biopsies in younger (n = 8; age, 23 ± 2 yrs) and older (n = 6; age, 85 ± 1 yrs) women prior to and following completion of bilateral knee extensions for 3 sets of 10 repetitions at 70% of their one repetition maximum strength (1-RM) . It was observed that at rest older women had a higher expression of myostatin compared to the younger, however the bout of resistance exercise had a similar effect on myostatin gene expression (2.2-fold down regulation at 4 hours post-exercise) for both age groups. Another study which compared sarcopenic and nonsarcopenic older and not older males (n = 31; age range: 55-70 yrs) found that 8-weeks of progressive resistance exercise training resulted in decreased myostatin at rest for both the sarcopenic and nonsarcopenic individuals . However, in contrast, a study investigating the effects of elastic band resistance training on circulating markers of muscle growth and degradation in older women (n = 91; mean age = 83.6 yrs, age range = 65-92 yrs) found that myostatin remained unchanged following 3 and 6-months of training . These two results combined suggest that myostatin levels may respond differently between older males and females completing resistance-exercise training; however, further research would be needed to confirm this. This could be explained by altered hormonal concentrations (such as testosterone and estrogen) between males and females and may also be explained by the vastly different age categories these two studies were completed in (i.e., males age range 55-70 years and females age range 65-92 years) [32,33].
Follistatin is a myostatin antagonist and also inhibits activin (another promoter of muscle catabolism) within skeletal muscle . Follistatin results in muscle hypertrophy from the inhibition of myostatin and activin and by promoting satellite cell proliferation . The up-regulation of follistatin is associated with satellite cell proliferation stimulated via testosterone . Additionally, follistatin increases myogenic differentiation . Therefore, follistatin may be an important myokine in skeletal muscle hypertrophy, while improving muscle healing from injury and disease .
The response of follistatin to resistance training programs may differ between sarcopenic and nonsarcopenic individuals. Following an 8-week progressive resistance training program in a mix of middle-age and older males (n = 31; age, 55-70 yrs), only the healthy, nonsarcopenic individuals, showed an elevated follistatin concentration post-training . Thus, if an individual already has low skeletal muscle mass, they may not respond as readily to resistance-exercise in terms of enhancing follistatin concentrations. This may be due to anabolic resistance (i.e., the lack of response to anabolic stimuli) that older sarcopenic males may possess . This may be further explained by the decrease in IGF-1 and decreased activation of the Akt/mTOR pathway in aging muscle . Another study investigated follistatin concentrations following 3 and 6-months of elastic band resistance training in older women (n = 91; mean age = 83.6 yrs, range = 65-92 yrs) . It was determined that the resistance training program resulted in increased circulating follistatin, but only at the 6-month mark of the training program. This proposes that it may take a longer period to see increased concentrations of follistatin from the resistance training stimulus in older women.
The myokine irisin is primarily recognized for its effect on converting white adipose tissue to brown adipose tissue (which is more metabolically active) . However, emerging evidence suggests irisin may also contribute to muscle hypertrophy . While undergoing myogenic differentiation, cultured human myocytes increase fibronectin type III domain-containing protein 5 (FNDC5) expression and irisin secretion . Additionally, when human myocytes are treated with irisin an increase in IGF-1 gene expression and a decrease in myostatin gene expression occurs . These findings suggest that irisin may contribute to muscle hypertrophy in response to resistance exercise.
The response of irisin to acute resistance exercise as well as resistance training programs in older adults has been investigated [11,40]. In both resistance untrained and trained states (i.e., before and after a 12-week resistance training program), younger males (n = 8; age: 24.8 ± 3.9 yrs) have greater concentrations of circulating irisin than older males (n = 7; age: 68.3 ± 5.0 yrs) . However, in the untrained state younger and older adults do not differ in their response to a bout of blood flow restricted resistance exercise but following a 12-week resistance training program differences appear where younger males have higher concentrations of circulating irisin immediately following, 24-hrs and 48-hrs following the blood flow restricted resistance exercise . Another study, also conducted in older males, randomized participants to a control group (n = 7; age: 61.9 ± 3.1 yrs) or a group which completed 12-weeks of resistance training (n = 10; age: 62.3 ± 3.5 yrs) and found that the resistance training program resulted in elevated resting serum irisin concentrations, as well as the irisin concentrations in the resistance training group were negatively correlated with the change in percent body fat over the 12-week program . This suggests that irisin may have a positive effect on reducing fat mass in older males completing a resistance training program.
2.5 Brain Derived Neurotropic Factor (BDNF)
Brain derived neurotrophic factor (BDNF) was initially recognized for its relationship with nervous system function, however BDNF and its receptors are expressed in skeletal muscle . This would suggest that BDNF could play an important role in skeletal muscle . In murine skeletal muscle, BDNF is present in satellite cells and is important for satellite cell differentiation and skeletal muscle regeneration . Injured murine muscle tissue depleted of BDNF has delayed expression of regeneration related molecules and formation of new muscle fibers . Exercise (cycling for 120 mins at 60% of maximal oxygen uptake) results in upregulation of BDNF expression in human skeletal muscle  and therefore may contribute to skeletal muscle and neuronal adaptations to aerobic training in older adults.
A group of cognitively healthy older adults (males, n = 5 and females, n = 5; age: 66.3 ± 5.3 yrs) had blood samples collected at rest and acutely following a resistance training protocol which was performed at study initiation and again following 8-weeks of resistance training . The authors identified an acute increase of circulating BDNF following resistance exercise, however there was no difference in systemic concentrations at rest or following the 8-week resistance training program. Another 12-week resistance training study randomized apparently healthy older adults (n = 56; age: 68 ± 5 yrs) to 3 days per week at either a high (2 sets of 10-15 repetitions performed at 80% of their 1-RM), low (1 set of 80-100 repetitions at 20% of their 1-RM) or mixed low-resistance (1 set of 60 repetitions at 20% 1-RM followed by 1 set of 10-20 repetitions at 40% 1-RM) and were instructed to reach volitional exhaustion in each set they completed . The study found that only the males in the group which performed the mixed low-resistance program increased resting serum BDNF, while no other changes were identified. These results suggest that BDNF secretion may be sex and resistance intensity dependent. However, contrasting these previous findings, evidence suggests that BDNF can acutely increase following resistance training, as well as be higher at rest following a resistance training program in women [47,48]. One study evaluated serum BDNF concentrations in older females (n = 20; age: 84 ± 8 yrs) from a nursing home who were randomly assigned to elastic resistance training or a control group . It was found that both at rest and following an acute bout of elastic resistance training BDNF was increased. Another study investigated the effects of a 12-week resistance training program (performed 3-days per week with elastic bands) in a group of 26 older females (age: 70.6 ± 6.2 yrs) with obesity (body fat percentage: 36.1 ± 2.5%) . The group which performed the resistance training had higher serum BDNF concentrations at rest, following the training program, compared to the females who did not. These results suggest that resistance exercise is beneficial for increasing BDNF concentrations in females which may have many positive effects on many physiological systems (for example: muscle and nerve tissue). In nervous tissue, BDNF is deemed one of the candidate molecules that may have an effect in enhancing neurogenesis and synaptic plasticity ; however, skeletal muscle derived BDNF may not be able to cross the blood-brain-barrier thus, may have limited effects in the central nervous system but, BDNF levels seem to be enhanced in human models of acute exercise in the central nervous system . In skeletal muscle tissue, BDNF may act in an autocrine role by enhancing lipid oxidation via adenosine monophosphate activated protein kinase (AMPK) which would increase the breakdown of intramuscular lipid stores .
Myokines are postulated to contribute to the hypertrophic effects of skeletal muscle associated with exercise  with many myokines preferentially up- or down-regulated in response to resistance exercise . Exercise induced myokine expression may be specifically valuable in older age because of the variety of therapeutic roles they may play in maintaining health with increasing age . This review highlighted the effects of resistance exercise on various myokines in older adults, and specifically their potential influence on skeletal muscle (see Table 1 for summary of discussed human studies). Sarcopenia is a concern in older age and is associated with additional health risks [1,2,3,4,5]. Resistance exercise is recognized as a potent stimulus for muscle hypertrophy, strength and protein synthesis which could mitigate strength loss, muscle atrophy and loss of function with aging . The current literature investigating the myokine response to acute and chronic resistance exercise in older adults is limited, but a further understanding of these proteins could be beneficial for identifying mechanisms for therapeutic targets. The current literature utilizes resistance training protocols of various frequencies, intensities, types (i.e., free weights, machines, elastic bands), and durations which may explain some of the contradicting findings. Identifying the optimal resistance training sessions and programs to stimulate hypertrophy related myokine secretion would improve recommendations for aging adults at risk of or experiencing the loss of muscle strength, muscle mass and function. It is suggested that further research around myokine biology in relation to resistance exercise will enhance our understanding of how myokines may influence skeletal muscle in a positive manner.
SMC conceptualized the manuscript. SMC and DMC contributed to writing of the original manuscript and have reviewed and agreed to the published version of the manuscript.
DMC is affiliated with the Pan Am Clinic Foundation which receives general education and research support from ConMed Linvatec, Ossur, Zimmer Biomet, and Arthrex. SMC declares no competing interests exist.
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