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Aims/Introduction Myopathy is a common complication of any diabetes type, consisting in failure to preserve mass and muscular function. Oxidative stress has been considered one of the main causes for this condition. This study aimed to search if Nicorandil, a KATP channel opener, could protect slow‐ and fast‐twitch diabetic rat muscles from oxidative stress, and to unveil its possible mechanisms. Materials and Methods Diabetes was induced in male Wistar rats by applying intraperitoneally streptozotocin (STZ) at 100 mg/kg doses. Nicorandil (3 mg/kg/day) was administered along 4 weeks. An insulin tolerance test and assessment of fasting blood glucose (FBG), TBARS, reduced (GSH), and disulfide (GSSG) glutathione levels, GSH/GSSG ratio, and mRNA expression of glutathione metabolism‐related genes were performed at end of treatment in soleus and gastrocnemius muscles. Results Nicorandil significantly reduced FBG levels and enhanced insulin tolerance in diabetic rats. In gastrocnemius and soleus muscles, Nicorandil attenuated the oxidative stress by decreasing lipid peroxidation (TBARS), increasing total glutathione and modulating GPX1‐mRNA expression in both muscle’s types. Nicorandil also increased GSH and GSH/GSSG ratio and downregulated the GCLC‐ and GSR‐mRNA in gastrocnemius, without significative effect on those enzymes’ mRNA expression in diabetic soleus muscle. Conclusions In diabetic rats, Nicorandil attenuates oxidative stress in slow‐ and fast‐twitch skeletal muscles by improving the glutathione system functioning. The underlying mechanisms for the modulation of glutathione redox state and the transcriptional expression of glutathione metabolism‐related genes seem to be fiber type‐dependent.

In response to diabetes mellitus, skeletal muscle is negatively affected, as is evident by reduced contractile force production, increased muscle fatigability, and increased levels of oxidative stress biomarkers. Apocynin is a widely used NADPH oxidase inhibitor, with antioxidant and anti-inflammatory potential. It has been effective for amelioration of a variety of disorders, including diabetic complications. Therefore, the present study was conducted to evaluate the effects and action mechanisms of apocynin in slow- and fast-twitch diabetic rat muscles. Male Wistar rats were rendered diabetic by applying intraperitoneally a single dose of streptozotocin (45 mg/kg). Apocynin treatment (3 mg/kg/day) was administered over 8 weeks. Fasting blood glucose (FBG), insulin tolerance and body weight gain were measured. Both slow (soleus) and fast (extensor digitorum longus, EDL) skeletal muscles were used for muscle function evaluation, oxidative stress markers, and evaluating gene expression using qRT-PCR. Treatment with apocynin significantly reduced FBG levels and enhanced insulin tolerance. Apocynin also prevented muscle contractile dysfunction in EDL muscle but had no significant effect on this parameter in soleus muscles. However, in both types of muscles, apocynin mitigated the oxidative stress by decreasing ROS levels and increasing total glutathione levels and redox state. Concomitantly, apocynin also statistically enhanced Nrf-2 and GLU4 mRNA expression and downregulated NOX2, NOX4, and NF-κB mRNA. Collectively, apocynin exhibits properties myoprotective in diabetic animals. These findings indicate that apocynin predominantly acts as an antioxidant in fast-twitch and slow-twitch muscles but has differential impact on contractile function.

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Cancer cachexia is a complex metabolic wasting disease that occurs in up to 80% of cancer patients and is responsible for about 20% of deaths in cancer patients. While research is growing, cancer cachexia remains a vastly underestimated and untreated condition. Current research shows that cardiac muscleis depleted during cancer cachexia but little research has been conducted examining the effects of sex on this phenomenon. PURPOSE: The purpose of this study was to examine the effects of sex on cardiac dysfunction during cancer cachexia and determine the underlying mechanisms responsible for this phenomenon. METHODS: Male and female LC3 Tg+ mice underwent a 3-week Lewis Lung Carcinoma (LLC; 1x10 6 in flank) protocol. Cardiac function was assessed via conscious echocardiography, and autophagic and inflammatory proteins were investigated for their possible role in cancer-mediated cardiac wasting. RESULTS: Echocardiography revealed that there was a significant (p<0.05) reduction in the fractional shortening in both males and females when comparing pre-and post-inoculation values. Furthermore, males exhibited a significantly greater degree of cardiac dysfunction compared to females after 3 weeks of tumor bearing (fractional shortening: males, -29% vs. female, -8%; P< 0.01). Autophagic flux analysis showed both male and female hearts exhibited a significant increase in late phase autolysosomes, with females exhibiting significantly (P< 0.05) more late phase puncta (P< 0.05). Similarly, tumor bearing females expressed significantly more cardiac LC3-II and FoxO3a compared to male tumor bearing mice. Interestingly, while both male and female tumor bearing groups showed increased NF-kB expression (not significant), only female tumor bearing mice exhibited a significant (P< 0.05) increase in IL-1beta expression. No significant difference in TNF-alpha levels was found when comparing tumor bearing males and females. CONCLUSION: Our data supports the idea that cardiac dysfunction is mediated by cancer cachexia and that certain autophagy and inflammatory pathways respond differently based on sex. This data can serve an important role in understanding how cancer cachexia presents and progresses differently based off sex and helps identify sex specific targets for therapeutic intervention.