Glycative Stress Research
Online edition : ISSN 2188-3610
Print edition : ISSN 2188-3602
Received : November 19, 2022
Accepted : December 6, 2022
Published online : December 31, 2022
doi:10.24659/gsr.9.4_199

Original article

Glycative stress and skeletal muscle dysfunctions;as an inducer of “Exercise-Resistance”
Tatsuro Egawa 1), Takeshi Ogawa 2), Takumi Yokokawa 3), Kohei Kido 4,5), Mami Fujibayashi 6)
Katsumasa Goto 7), Tatsuya Hayashi 2)1) Laboratory of Health and Exercise Sciences, Graduate School of Human and Environmental Studies, Kyoto University, Kyoto, Japan.
2) Laboratory of Sports and Exercise Medicine, Graduate School of Human and Environmental Studies, Kyoto University, Kyoto, Japan.
3) Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan.
4) Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Japan.
5) Institute for Physical Activity, Fukuoka University, Fukuoka, Japan.
6) Faculty of Agriculture, Setsunan University, Osaka, Japan.
7) Department of Physiology, Graduate School of Health Sciences, Toyohashi SOZO University, Aichi, Japan.

Abstract

Skeletal muscle, the largest tissue in the body, is often overlooked for its role as a locomotor organ, however over the past few
decades it has been revealed that it also has an important role as a metabolic organ. In recent years, its role as an endocrineorgan that controls the homeostatic functions of organs throughout the body mediated by myokine secretion has come underclose scrutiny. Skeletal muscle is indispensable for our daily life activities, and in order to maintain its function, it is necessary
to understand the factors that deteriorate muscle function and establish a countermeasure. Glycative stress has recently
received attention as a factor that impairs skeletal muscle function. Accumulation of advanced glycation end products (AGEs)
in skeletal muscle impairs contractile function and myogenic potential. Furthermore, AGEs in the blood elicit inflammatory
signals through binding to RAGE (Receptor for AGEs) expressed on muscle cells, resulting in muscle proteolysis. Habitual
exercise is important to mitigate the negative effects of such glycative stress on skeletal muscle. On the other hand, it is known
that the beneficial effects of exercise vary among individuals. The state in which the effects of exercise are difficult to obtainis called "exercise-resistance," and we hypothesize that glycative stress may be one of the causes of exercise-resistance. In
this paper, we will discuss the possibility of glycative stress as an inducer of exercise resistance and summarize its impacts onskeletal muscle.

KEY WORDS: glycative stress, advanced glycation end products (AGEs), skeletal muscle, exercise resistance, sarcopenia
Introduction:
Importance of skeletal muscle in healthmaintenance and promotion

Skeletal muscle is the largest tissue in the body,accounting for about 40 % of total body weight. In addition
to its role as a locomotor that generates physical activity,
skeletal muscle contributes significantly to our lifesustaining activities as a metabolic and endocrine organ. For
example, 80 % of the glucose in the blood is taken up byskeletal muscle and used for energy production or stored as

glycogen. Therefore, a decline in skeletal muscle metabolic
function leads to systemic glucose intolerance, which isa factor in triggering metabolic diseases, i.e., diabetes. In
recent years, it has become clear that myokines, bioactive
substances secreted by skeletal muscle, are involved in theregulation of the functions of various organs in the body aswell as skeletal muscle. After the age of 50, skeletal muscle
mass declines by 1-2 % per year and muscle strength by 1. 55 % 1), and therefore, maintaining the quantity and quality ofskeletal muscle is a prerequisite for healthy longevity ( Fig. 1)

Correspondent: Tatsuro Egawa, Ph.D.
Laboratory of Health and Exercise Sciences,
Graduate School of Human and Environmental Studies, Kyoto University,
Yoshida-nihonmatsu-cho, Sakyo-ku, Kyoto 606-8501, Japan.
TEL : +81-75-753-6613 e-mail: egawa.tatsuro.4u@kyoto-u.ac.jp
Co-authors; Ogawa T, taketakemanu823@gmail.com;
Yokokawa T, yokokawa.takumi.8w@kyoto-u.ac.jp; Kido K, kohei.kido110@gmail.com;
Fujibayashi M, mami.fujibayashi@setsunan.ac.jp; Goto K, goto@sozo.ac.jp;
Hayashi T, tatsuya@kuhp.kyoto-u.ac.jp_ 19 9 _Glycative Stress Research 2022; 9 (4): 199-205(c) Society for Glycative Stress ResearchGlycative Stress as an Inducer of “Exercise-Resistance”

Fig. 1. Skeletal muscle and metabolic health.

Skeletal muscle has an important responsibility for maintaining our health as not only locomotor system but
also metabolic and endocrine systems. NAFLD, non-alcoholic fatty liver disease.

Glycative stress and impairment of motorand skeletal muscle function

Advanced glycation end product (AGE) modificationof proteins is an irreversible reaction that is essentiallymetabolized by the proteolytic system. However, as the protein
turnover function declines with age, the accumulation of
AGEs in the body progresses over time, adversely affecting
biological functions. The relationship between age-related
AGE accumulation and motor and skeletal muscle function
was first reported by a research team led by Dr. Richard
Semba, Johns Hopkins University, Baltimore, MA, USA, whofound that elevated blood N ε -(carboxymethyl) lysine (CML)
levels were a risk factor for impaired muscle strength andwalking ability 2 - 4). Subsequent epidemiological studies in
middle-aged and elderly subjects have confirmed that elevatedblood AGEs and subcutaneous AGEs (skin autofluorescence:
SAF ) correlate with impaired muscle strength and physicalfunction ( Table 1). The accumulation of AGEs in the body is
considered to be a biomarker of reduced motor and skeletal
muscle function.
Recent studies have confirmed that an association
exists between subcutaneous AGE accumulation status andimpaired motor and skeletal muscle function in middle-aged
and older adults as well as in children and young adults.
In a study of 1,075 children (6-8 years), a Swiss researchteam found that children with higher levels of SAF hadlower endurance capacity 5). Also, our study of 20 college
students (18-20 years) confirmed a negative correlation
between SAF and leg muscle strength 6). Namely, the impactsof glycative stress on motor and skeletal muscle function

may occur regardless of age. Whereas, a study of 1,542
adolescents reported that low muscle strength promotes AGE
accumulation rather than AGE accumulation induces muscle
weakness 7), thus, further research is needed to clarify thecausal relationship between the two.

Molecular mechanisms ofglycation-induced decrease in motor andskeletal muscle function

The first factor that causes AGE accumulation to impair
motor and skeletal muscle function is that muscle contractile
proteins, i.e., myosin, actin, tropomyosin, are modified byglycation, resulting in impaired contractile function 8-11). It
has also been suggested that changes in extracellular matrix
structure, decreased ATPase activity 9, 12), and impaired motor
neurotransmission 13) are also involved ( Fig. 2).
Our recent study reports that myogenesis and protein
synthesis signaling are affected by glycative stress. In thisstudy, mice fed a diet containing 5 times the normal level ofAGEs for 16 weeks showed decreased expression of myogenic
factor 5 (Myf5) and myogenic differentiation 1 (MyoD), whichplay a role in promoting myogenesis; furthermore, insulinlike growth factor 1 (IGF-1) signaling, which plays a rolein promoting protein synthesis, was attenuated, resulting indecreased muscle mass 14, 15). In an experiment using miceintaking methylglyoxal (MGO), a precursor of AGEs, for
20 weeks, gene expression of the inflammatory cytokinesinterleukin (I L)-1β and IL-6 increased in association with_ 200 _Glycative Stress Research

Table 1. Association between glycative stress and muscle function

Reference

Characteristics

AGE type

Impacts on muscle function

Dalal et al., 2009 2)

women, age ≥ 65 years (n = 559)

serum CML

lower grip strength

Semba et al., 2010 3)

age ≥ 65 years (n = 944)

plasma CML

slower walking speed

Momma et al., 2011 30)

men, median age 46.0 years (n = 232)

SAF

Sun et al., 2012 4)

women, age ≥ 65 years (n = 394)

serum CML

severe walking disability

Whitson et al., 2014 31)

mean age 78.1 ± 4.8 years (n = 3,373)

serum CML

physical frailty

SAF

lower muscle mass

Kato et al., 2017 32)

men, mean age 57 ± 10 years;

women, 60 ± 11 years (n = 132)

lower grip strength and leg
extension power

Mori et al., 2017 33)

mean age 55.7 ± 10.3 years (n = 36)

SAF

lower knee extension strength

Drenth et al., 2018 34)

age ≥ 65 years (n = 5,624)

SAF

lower physical function

Ebert et al., 2019 35)

aged 43–83 years (n = 1,770)

plasma AGE

lower physical function

age 72.7 ± 10.1 years (n = 47); controls,

serum pentosidine

lower muscle massMori et al., 2019 37)

mean age 63.2 ± 12.3 years (n = 166)

SAF

Yang et al., 2019 38)

age ≥ 65 years (n = 104)

urinary CML

lower grip strength

Tabara et al., 2019 39)

mean age 57.8 ± 12.4 years (n = 9,203)

SAF

lower muscle mass and grip strength

Eguchi et al., 2019 36)

Moriwaki et al., 2021 40)

women with sarcopenia,

age 77.2 ± 7.2 years (n = 23)

men, 75.0 ± 8.9 years (n = 157);

urinary pentosidine

women, 73.6 ± 8.1 years (n = 97)

ower muscle mass, strength, andphysical performancewalking disability and lower grip
strength

Results are expressed as mean ± SD. AGE, advanced glycation end product; CML, N ε- (carboxymethyl) lysine; SAF, skin autofluorescence; SD, standard
deviation.

muscle mass loss 16), suggesting that glycative stress may
induce protein catabolism through inflammatory signals.
The changes observed in these studies occurred
primarily in fast-twitch muscle, suggesting that there may be
a muscle-type specificity in the effects of glycative stress on
skeletal muscle. These impairments in myogenesis, protein
synthesis, and inflammation-induced catabolism that occur
predominantly in fast-twitch muscle may be triggers for theage-related selective loss of fast-twitch muscle function, socalled sarcopenia.
Whereas, another of our studies reported that glycative
stress is involved in disuse muscle atrophy, which occurs
mainly in slow muscle 17). In this study, mice subjected to a
1-week hindlimb suspension induced disuse atrophy, resulting
in slow-twitch muscle-dominant atrophy and increased

receptor for AGEs (RAGE) expression. In addition,
the administration of RAGE antagonists decreased theaccumulation of AGEs in muscle and partially relieved disusemuscle atrophy. In short, disuse muscle atrophy is thought tobe induced by increased RAGE-dependent glycative stress.

Glycative stress as an inducer of exercise
resistance

There is no doubt that exercise is a powerful healthpromoting biological stimulus. Indeed, habitual exercise isalso effective in reducing glycative stress 18, 19). However, it isalso true that there are individual differences in the health-_ 2 01 _Glycative Stress as an Inducer of “Exercise-Resistance”

Fig. 2. Molecular mechanisms underlying AGEs-induced muscle dysfunctions.

Myf5, myogenic factor 5; MyoD, myogenic differentiation 1; IGF-1, insulin-like growth factor 1; p70S6K, 70kDa
ribosomal protein s6 kinase; ERK, extracellular signal-regulated kinase.

promoting effects of exercise. Concurrently, a wide range ofindividual differences are observed among diabetics andthe elderly, and it is known that about one out of every fivepeople is unable to obtain sufficient exercise benefits 20-23).
Such a condition in which it is difficult to obtain the benefits
of exercise, namely the condition in which physical adaptation
to exercise is difficult to occur, is called "exercise-resistance",
and those who are less likely to develop it are called "nonresponder". The factors thought to mediate exercise resistanceinclude congenital factors, e.g., age, race, genetic predisposition,
and acquired factors, e.g., type and intensity of exercise,dietary habits, sleep habits, insulin sensitivity 20, 23). Theirdefinitions, however, are not clear.
For this factor, we focus on methylglyoxal (MGO), oneof the products of the glycolytic system. MGO is a highly
reactive dicarbonyl compound and is 20,000 times morereactive than glucose in glycation reactions 24). It has also beenreported that MGO induces mitochondrial dysfunction andinflammation in skeletal muscle cells and other tissues 25, 26),
suggesting that it may be a factor that interferes with normal
adaptive changes in the body. In our study in which MGOadministered mice underwent spontaneous running training
for 4 weeks, the increase in mitochondrial respiratory chain
complexes in skeletal muscle associated with exercise
training was suppressed, despite no difference in locomotor
activity compared to control mice that did not receive MGO 27)(Fig. 3 ). Also, the same was true for peroxisome proliferatoractivated receptor γ coactivator-1α (PGC1α) expression, amaster regulator of mitochondrial biosynthesis, and citratesynthase activity. This means that mitochondrial adaptationis less likely to occur during exercise in the presence of
higher-than-normal levels of MGO. Other findings include a
broad attenuation of adaptive responses induced by exercise,such as increased phosphorylation of insulin signaling
molecules, increased expression of heat shock protein(HSP72), and increased expression of glyoxalase 1, a MGOmetabolizing enzyme. Although the molecular mechanism
by which MGO causes such exercise resistance is not clear,this is the first evidence that glycative stress may influence
the health-promoting effects of exercise.
Our results on the effects on strength training are alsointeresting. In a mouse muscle training model in which
compensatory hypertrophy of the plantaris muscles of thelower limb was induced by synergist muscle ablation, theadministration of glyceraldehyde-derived AGEs (0.5 mg/g/
day) once a day for one week before treatment resulted ininhibition of compensatory muscle hypertrophy and increase
in myonuclei 28). This means that AGEs have exercise
resistance properties that interfere with the effects of muscle
training. Unexpectedly, a part of mice treated with AGEs
showed disruption of muscle cell membranes with muscle
hypertrophy ( Egawa et al., unpublished data). In a study
using cultured skeletal muscle cells, it was also confirmedthat the addition of AGEs causes weakening of muscle cell
membranes, suggesting that glycative stress causes exercise
resistance and concurrently damages muscle cell structure.

_ 202 _Glycative Stress Research

Fig. 3. Methylglyoxal suppresses exercise-induced mitochondrial adaptations in skeletal muscle.

Methylglyoxal (MGO) intake (1% drinking water) suppressed 4-week voluntary exercise-induced upregulation of peroxisome
proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) and mitochondria complex proteins (CI, CII, CIII, CIV, and CV)
in plantaris muscle but not in soleus muscle. Data are presented as mean ± SD (n = 6 per group). Individual data points are indicatedon the bar graph. Representative immunoblots are shown. Statistical significance was analyzed using two-way ANOVA with exercise
and MGO treatment as main factors. *: P < 0.05 with simple effects tests, n.s.: not significant. Sed, sedentary control group; Ex,voluntary exercise group. This figure was adapted from Egawa et al. 27) with permission of the publisher.

Summary and conclusion
Musculoskeletal diseases, as typified by sarcopenia, areimportant factors that lead to conditions requiring long-termcare. As an endocrine organ, skeletal muscle communicateswith various organs throughout the body to maintainphysiological functions. Namely, quantitative and qualitative
deterioration of skeletal muscles leads to deterioration of theentire body. As shown in this text, glycative stress appears
to adversely affect skeletal muscle regardless of age. We
speculate that glycative stress in skeletal muscle, which
begins in youth, causes continuous and gradual damage tometabolic molecules and muscle cell structures, and that thisdamage accumulates in old age, eventually leading to muscle

atrophy and loss of muscle function. Therefore, countering
glycative stress is an issue that should be addressed fromyoung adulthood, not from middle age. The first strategy tocounteract this stress in skeletal muscle would be exercise.
However, since glycative stress causes exercise-resistance,
exercise under increasing stress may not be sufficiently
effective (Fig. 4 ). Fortunately, in our report, muscle strength
training three times a week for 12 weeks in male university
students showed a muscle-strengthening effect regardlessof their glycative stress status 29). In conclusion, expectedly,
taking measures against glycative stress centered on exercise
from young age will lead to the prevention of glycative
stress-related diseases that become apparent in old age.

_ 203 _Glycative Stress as an Inducer of “Exercise-Resistance”

Fig. 4. Possible involvement of glycative stress in exercise resistance.

Exercise-induced skeletal muscle adaptations may not occur in some cases, a condition known as exercise-resistance (also called
non-responder). Exercise-resistance means that adaptive responses driven by exercise are diminished due to the heterogeneity offactors such as endogenous factors (age, sex, etc.), exogenous factors (exercise intensity, duration, etc.), and molecular responses(proteins, genes, metabolites, etc.). Glycative stress may be a new exogenous factor that reflects exercise-resistance.

Acknowledgement

Conflict of interest declaration

This work was supported by Grants-in-Aid for Scientific
Research (JSPS KAKENHI) (22H03474, 22K18413, 22K19722,
22K19750, 21H03319, 19KK0254) and the Research Institutefor Production Development (RID). Part of this study waspresented at the 25th Meeting of Society for Glycative StressResearch on September 10, 2022, Kyoto, Japan.

All authors declare that they have no conflicts ofinterest.

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