**4.1 AGEs accumulation and skeletal muscle dysfunction**

In this about 10 years, epidemiological studies have reported the relationship between AGEs level in the body and skeletal muscle functions. The first report by

#### *The Effect of Glycation Stress on Skeletal Muscle DOI: http://dx.doi.org/10.5772/intechopen.97769*

Dalal et al. [6] found an association between elevated serum CML level and poor grip strength in 559 older women with physical disability (≥ 65 years old). A similar result was observed in the InCHIANTI study, which is a population-based prospective cohort study conducted in the Chianti region in Italy. The study showed that elevated plasma CML level was at high risk of slow walking speed (odds ratio 1.56, 95% confidence interval 1.02–2.38, P = 0.04) in 944 older community-dwelling adults (≥ 65 years old) [7]. Sun et al. [9] also reported that elevated serum CML level was a risk factor for developing severe walking disability. In the study, which had a 30-month follow-up in 394 older women (≥ 65 years old), it was shown that compared with the group of lower three quartiles of CML, the patients in the group of highest quartile of CML were more likely to develop severe walking disability (hazard ratio 1.54, 95% confidence interval 1.04–2.29, P = 0.03). A communitybased cross-sectional study by Yang et al. [16] showed that urinary CML level was negatively associated with grip strength among 41 older women but not 63 older men (≥ 65 years old). Furthermore, the joint association of urinary CML level and mobility function was correlated with the risk of developing sarcopenia among older adults (odds ratio 13.76, 95% confidence interval 1.03–183.83, P < 0.05). In addition to CML, increased serum pentosidine, a well-known AGEs found in the plasma and tissues of diabetic and uremic subjects [40], was shown to be negatively associated with skeletal muscle mass in 133 postmenopausal women with type 2 diabetes (mean age 66.8 years) [10] and in 70 elderly women with or without sarcopenia (≥ 53 years old) [17].

These findings are also supported by studies using non-invasive AGEs measurement methods. Because several AGEs have characteristic fluorescence, the measurement of skin autofluorescence (SAF) is often adopted to assess the level of AGEs in the body. Momma et al. [8] investigated the relationship between SAF and muscle strength and power in 232 adult men (median age 46.0 years) and found that participants with higher SAF had lower grip strength and leg extension power. Kato et al. [11] also reported that SAF was significantly higher in the low skeletal muscle index group compared with the normal skeletal muscle index group among 132 elderly people (mean age 59.0 years). Moreover, SAF was shown to be an independent factor associated with low skeletal muscle index (odds ratio 15.7, 95% confidence interval 1.85–133.01, P = 0.012). The negative association between SAF and muscle mass (odds ratio 1.48, 95% confidence interval 1.23–1.78, P < 0.001), grip strength (odds ratio 1.98, P = 0.003), hip flexion strength (odds ratio 1.50, P = 0.012), and hip abduction strength (odds ratio 1.78, P = 0.001) was found among 9,203 participants (mean age 57.8 years) in the Nagahama study, which is a large-scale population-based cohort study in Japan [13]. Another large populationbased cohort study in the Netherlands, the Lifelines study also demonstrated the relationship between SAF and poor physical functioning among 5,624 participants (≥ 65 years old) [14]. In a study of diabetic patients, Mori et al. [12] reported that knee extension power was negatively correlated with SAF among 36 patients with type 1 diabetes (mean age 55.7 years). They subsequently reported that SAF was the independent determinant for skeletal muscle mass index (odds ratio 6.38, 95% confidence interval 1.93–21.08, P < 0.05), grip strength (odds ratio 3.55, 95% confidence interval 1.57–8.00, P < 0.05), knee extension power (odds ratio 3.68, 95% confidence interval 1.87–7.23, P < 0.05), and sarcopenia (odds ratio 7.73, 95% confidence interval 2.13–28.02, P < 0.05) among 166 patients with type 2 diabetes (mean age 63.2 years) [15]. Collectively, accumulation of AGEs may be a better predictor of skeletal muscle dysfunctions during aging process. Furthermore, recent our preliminary study found that SAF was negatively associated with leg extension power in 20 health young men (mean age 19.0 years) (**Figure 2**). Therefore, glycation stress may affect muscle strength even in young people, and it is considered

#### **Figure 2.**

*Correlation between skin autofluorescence (SAF) and leg extension power. The subjects were 20 healthy young men, and after measuring the subcutaneous glycation state with an AGEs sensor (RQ-AG01J, Sharp Life Sciences, Hyogo, Japan), the maximum lift weight of leg extension was measured. Statistical significance was assessed using Pearson's correlation.*

that grasping the glycation stress state not only from the elderly but also from the young age can contribute to the prevention of future muscle dysfunctions.

#### **4.2 AGEs modification of contractile proteins in skeletal muscle**

Decreased skeletal muscle quantity is deemed a crucial cause of aging-associated muscle dysfunctions. However, recent evidence suggests that the quality of muscle tissue is more functionally relevant than its quantity. Muscle contractile properties are identified as an important determinant of functional limitations in older adults [41]. In this context, several studies have focused on the effect of intracellular glycation on protein structure and function in skeletal muscle. Syrovy and Hodny [42] first reported in 1993 that incubation of myofibrils with ribose promoted the glycation of myofibrillar proteins such as myosin heavy chain, α-actinin, actin, and tropomyosin, accompanied by reduced ATPase activity. The decrease in ATPase activity associated with the glycation is supported by several subsequent studies [43–45]. A major component of skeletal muscle, myosin contains 201 lysine residues and offers numerous potential sites for glycation. In fact, Ramamurthy et al. [46] demonstrated that glucose exposure to rodent skeletal muscle fiber induced myosin structural change and reduction of shortening velocity of myosin. The study is the first report to show the glycation-induced protein structural and functional changes in skeletal muscle. Furthermore, some researchers have found that actin and connective tissues were also modified with AGEs in skeletal muscle of old rats [47] and human [48]. Structural or chemical changes in actin, myosin, and extracellular matrix are likely to deteriorate muscle function by affecting actomyosin ATPase activity or stiffness [49, 50]. Our preliminary experiment also found that 45 AGEs-modified proteins were increased in skeletal muscle of old mice (24-month age) compared with that of young adult mice (6-month age) (unpublished data). These intracellular or extracellular AGEs modifications of skeletal muscle proteins may be a potent factor of agingassociated skeletal muscle dysfunctions.
