Background and objectives: Muscle wasting, a common complication in chronic kidney disease (CKD), contributes to poor outcomes. Mitochondrial biogenesis is critical for the maintenance of skeletal muscle function and structural integrity. The present study-a secondary analysis from a published randomized controlled trial-examined the effect of resistance exercise training on skeletal muscle mitochondrial (mt)DNA copy number and determined its association with skeletal muscle phenotype (muscle mass and strength).Design, setting, participants, & measurements: Twenty-three patients with moderate-to-severe CKD were randomized to resistance training (n ‫؍‬ 13) or an attention-control (n ‫؍‬ 10) group for 12 weeks. After a run-in period of a low-protein diet that continued during the intervention, mtDNA copy number in the vastus lateralis muscle was estimated by quantitative real-time PCR at baseline and 12 weeks.Results: Participants mean age was 64 ؎ 10 (SD) years and median (interquartile range, IQR) GFR 27.5 (37.0) ml/min. There were no differences between groups at baseline. Median (IQR) mtDNA copy number was 13,713 (10,618). There was a significant increase in muscle mtDNA with exercise compared with controls (1306 [13306] versus ؊3747 [15467], P ‫؍‬ 0.01). The change in muscle mtDNA copy number was positively correlated with previously reported changes in types I and II muscle fiber cross-sectional area.Conclusions: In this pilot study, resistance training was highly effective in enhancing mitochondrial content in patients with moderate-to-severe CKD. This finding suggests that the mitochondrial dysfunction observed with chronic disease could potentially be restored with this exercise modality and should be investigated further.

We examined the expression of the sodium-dependent glucose co-transporter system (hSGLT3) in skeletal muscle of Hispanic older adults with type 2 diabetes. Subjects (65±8 yr) were randomized to resistance training (3x/wk, n=13) or standard of care (controls, n=5) for 16 weeks. Skeletal muscle hSGLT3 and GLUT4 mRNA transcript levels were determined by real time RT-PCR. hSGLT3 transcripts increased by a factor of ten following resistance training compared to control subjects (0.10, P=0.03). There were no differences in GLUT4 mRNA expression levels between groups. Protein expression levels of these transporters were confirmed by immunohistochemistry and Western blotting. hSGLT3 after resistance exercise was found not to be co-localized with the nicotinic acetylcholine receptor. The change in hSGLT3 transcript levels in the vastus lateralis muscle was positively correlated with glucose uptake, as measured by the change in muscle glycogen stores (r=0.53, P=0.02); and with exercise intensity, as measured by the change in muscle strength (r=0.73, P=0.001). Group assignment was be the only independent predictor of hSGLT3 transcript levels, explaining 68% of its variability (P=0.01). Our data show that hSGLT3, but not GLTU4, expression was enhanced in skeletal muscle after 16 weeks of resistance training. This finding suggests that hSGLT3, an insulin-independent glucose transporter, is activated with exercise and it may play a significant role in glycemic control with muscle contraction. The hSGLT3 exact mechanism is not well understood and requires further investigation. However its functional significance regarding a reduction of glucose toxicity and improvement of insulin resistance is the subject of ongoing research.

The treatment of diabetes has been mainly focused on maintaining normal blood glucose concentrations. Insulin and hypoglycemic agents have been used as standard therapeutic strategies. However, these are characterized by limited efficacy and adverse side effects, making the development of new therapeutic alternatives mandatory. Inhibition of glucose reabsorption in the kidney, mediated by SGLT1 or SGLT2, represents a promising therapeutic approach. Therefore, the aim of the present study was to evaluate the effect of thioglycosides on human SGLT1 and SGLT2. For this purpose, stably transfected Chinese hamster ovary (CHO) cells expressing human SGLT1 and SGLT2 were used. The inhibitory effect of thioglycosides was assessed in transport studies and membrane potential measurements, using α-methyl-glucoside uptake and fluorescence resonance energy transfer, respectively. We found that some thioglycosides inhibited hSGLT more strongly than phlorizin. Specifically, thioglycoside I (phenyl-1'-thio-β-D-glucopyranoside) inhibited hSGLT2 stronger than hSGLT1 and to a larger extent than phlorizin. Thioglycoside VII (2-hydroxymethyl-phenyl-1'-thio-β-D-galacto-pyranoside) had a pronounced inhibitory effect on hSGLT1 but not on hSGLT2. Kinetic studies confirmed the inhibitory effect of these thioglycosides on hSGLT1 or hSGLT2, demonstrating competitive inhibition as the mechanism of action. Therefore, these thioglycosides represent promising therapeutic agents for the control of hyperglycemia in patients with diabetes.

Small concentrations of ethanol (1 mM) induced apoptosis in HepG2 MCTS with a concomitant inhibition on outgrowth potential, accompanied with a low degree of necrosis. These findings suggest that low concentrations of ethanol may already be sufficient for the treatment of hepatocellular carcinoma.