**5. Therapeutic perspectives for AGEs-induced skeletal muscle dysfunctions**

AGEs-RAGE axis seems to be the most contributor to skeletal muscle dysfunctions under glycation stress condition [66]. Recently, Chiappalupi et al. [67] demonstrated that cancer cachexia-induced muscle wasting and inflammatory responses were prevented in RAGE-null mice. In this regard, several RAGE antagonists were used for preclinical and clinical studies [68, 69]. For example, FPS-ZM1, which was identified by screening 5,000 compounds for their ability to inhibit RAGE and amyloid-β interaction, can block amyloid-β-induced cellular stress [70]. Azeliragon, which is an orally-active small-molecule antagonist of RAGE, improves cognitive function in Alzheimer disease patients by inhibiting inflammation and amyloid-β accumulation [71]. As our study showed, RAGE inhibition by FPS-ZM1 could prevent disuse-induced muscle atrophy [62]. Potentially, these RAGE inhibitors might be useful for various skeletal muscle atrophy.

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

#### **Figure 6.**

*The phosphoproteins related to insulin/insulin-like growth factor-1 (IGF-1) signaling. C2C12 myotubes on day 4 of differentiation were incubated with glyoxylic acid-derived AGEs, pyruvate- derived AGEs, glycolaldehyde- derived AGEs, glucose- derived AGEs, or BSA at 0.1 mg/mL for 24 h. After that, reverse phase protein array analysis was performed. The phosphoproteins related to insulin/IGF-1 signaling are represented as the relative log fold-change (FC) values. This figure was adapted from Egawa et al. [64] with permission from the publisher. IRS-1, insulin receptor substrate-1; IGF-1, insulin-like growth factor-1; GSK, glycogen synthase kinase; mTOR, mammalian target of rapamycin; 4E-BP1, eukaryotic translation initiation factor 4E binding protein- 1; eIF, eukaryotic translation initiation factor; eEF2k, eukaryotic elongation factor- 2 kinase.*

Plant-derived phytochemicals are also potentially beneficial for maintaining muscle functions. Screening of 536 kinds of plants has confirmed anti-glycation activity in more than 100 kinds of materials [72]. Recent our study [73] found that propolis, a natural resinous substance produced by honeybees, has an inhibitory effect on AGEs formation. Furthermore, propolis intake (0.1%-containing diet) for 20 weeks under glycation stress conditions from methylglyoxal exposure prevented intracellular MG-H1 accumulation and inflammatory cytokine expressions in mouse skeletal muscle (**Figure 7**).

In addition to phytochemicals, organic compound with anti-glycation effect, pyridoxamine has been shown to inhibit diabetes-related muscle dysfunctions. Muellenbach et al. [74] first showed that treatment with pyridoxamine (60 mg/kg i.p. injection) for 6 weeks improved insulin-stimulated glucose transport in the skeletal muscle of obese Zucker rats. In a study by Hagiwara et al. [75] using a high-fat diet fed rats, it was shown that 12-week treatment with pyridoxamine (300 mg/kg/day in drinking water) attenuated reductions in Akt phosphorylation and GLUT4 expression in the plasma membrane of skeletal muscle. Mastrocola et al. [76] demonstrated that pyridoxamine treatment to rats fed a high-fructose diet (60% of calories) for 12 weeks suppressed CML accumulation, RAGE upregulation, sirtuin-1 reduction, mitochondrial dysfunction, and contractile dysfunction in skeletal muscle. These

#### **Figure 7.**

*The content of methylglyoxal (MGO)-derived AGEs and mRNA expression of interleukin (IL)-1β, IL-6, tolllike receptor 4 (TLR4), and receptor for AGEs (RAGE) in the extensor digitorum longus muscles. The muscles were dissected from mice treated with or without propolis (0.1%)-containing diet or MGO (0.1%)-containing drinking water for 20 weeks. Data are expressed as means ± SE; n = 3–6 per group. \* P < 0.05 between the groups. Statistical significance was analyzed using Tukey–Kramer multiple comparisons tests. This figure was adapted from Egawa et al. [73] with permission from the publisher.*

results suggest that even in situations where glycation stress increase such as high-AGEs diet intake, skeletal muscle dysfunctions can be prevented by simultaneously ingesting compounds and foods that have anti-glycation effects.
