Subcutaneous Infusion of DNA-Aptamer Raised against Advanced Glycation End Products Prevents Loss of Skeletal Muscle Mass and Strength in Accelerated-Aging Mice

Abstract

We have developed DNA aptamers that can inhibit the toxic effects of advanced glycation end products (AGE-Apts). We herein evaluated the effects of AGE-Apts on muscle mass and strength in senescence-accelerated mouse prone 8 (SAMP8) mice. Eight-month-old male SAMP8 mice received subcutaneous infusion of control DNA aptamers (CTR-Apts) or AGE-Apts. Mice in an age-matched senescence-accelerated mouse resistant strain 1 (SAMR1) group were treated with CTR-Apts as controls. The soleus muscles were collected after the 8-week intervention for weight measurement and histological, RT-PCR, and immunofluorescence analyses. Grip strength was measured before and after the 8-week intervention. AGE-Apt treatment inhibited the progressive decrease in the grip strength of SAMP8 mice. SAMP8 mice had lower soleus muscle weight and fiber size than SAMR1 mice, which was partly restored by AGE-Apt treatment. Furthermore, AGE-Apt-treated SAMP8 mice had a lower interstitial fibrosis area of the soleus muscle than CTR-Apt-treated SAMP8 mice. The soleus muscle levels of AGEs, oxidative stress, receptor for AGEs, and muscle ring-finger protein-1 were increased in the CTR-Apt-treated mice, all of which, except for AGEs, were inhibited by AGE-Apt treatment. Our present findings suggest that the subcutaneous delivery of AGE-Apts may be a novel therapeutic strategy for aging-related decrease in skeletal muscle mass and strength.

DNA Aptamer Raised against Advanced Glycation End Products Improves Sperm Concentration, Motility, and Viability by Suppressing Receptors for Advanced Glycation End Product-Induced Oxidative Stress and Inflammation in the Testes of Diabetic Mice

“…These observations suggest that increased AGE accumulation levels in the diabetic testes under insulin-resistant and hyperglycemic conditions could stimulate RAGE gene expression via oxidative stress generation in a positive feedback manner, which is a molecular target of the AGE-Apt treatment-induced improvement of seminiferous tubular dilation and sperm abnormalities. This study revealed that testicular AGE accumulation per se was not affected by the 6-week treatment with AGE-Apt, which was consistent with the present finding, indicating that AGE-Apt treatment suppressed oxidative stress and Rage upregulation in soleus muscles but did not affect skeletal muscular AGE accumulation in a mouse model of sarcopenia [41]. Accordingly, AGE-Apt functions as a blocker of the binding of AGEs to RAGE, which could subsequently reduce oxidative stress generation and inflammation in the diabetic testes, but it did not sufficiently inhibit oxidative-stress-induced AGE formation under insulin-resistant conditions in our model.…”

“…AGEs have been shown to induce oxidative stress generation and inflammatory responses, such as Mcp-1 and Tnf-α gene expressions, through their interaction with RAGE in various cell types [ 12 , 13 , 14 ]. Furthermore, AGEs are reported to upregulate RAGE expression via oxidative stress generation, thereby forming a positive feedback loop between AGEs and RAGE-induced oxidative stress [ 40 , 41 ]. The present study revealed increased gene expression levels of Rage following AGE accumulation in the testes of 4-week-old DM mice.…”

“…The rest of the non-DM mice at 7 weeks of age were assigned to the CTR-Apt treatment group. Aptamers were continuously infused in mice at 10 pmol/g body weight/day for 6 weeks via osmotic pumps implanted under the dorsal skin [ 41 ].…”

“…The sample size was calculated to minimize the number of animals based on our previous studies [ 28 , 29 , 30 , 31 , 41 ]. Data are expressed as the mean ± standard deviation.…”