High-dose vitamin D administration and resistance exercise training attenuate the progression of obesity and improve skeletal muscle function in obese p62-deficient mice.

Vitamin D (VitD) possesses antiadipogenic and ergogenic properties that could be effective to counteract obesity-related adverse health consequences. Therefore, our overall hypothesis was that VitD could ameliorate obesity-induced insulin resistance, systemic inflammation, and loss of skeletal muscle mass and function in an obesity animal model, p62-deficient mice. Furthermore, it was hypothesized that resistance exercise training (RT) could enhance the benefits of VitD by upregulating protein expression of vitamin D receptor in skeletal muscle. Forty 24-week-old male p62-deficient mice were assigned to the following 4 groups (10/group) for a 10-week intervention: control (p62C, no treatment), VitD (VD, 1000 IU vitamin D3/kg/d), RT (ladder climbing, 3 times per week), or combined treatment (VRT, VD + RT). Serum VitD levels increased in VD and VRT (P < .05). Total body mass increased in p62C, VD, and VRT, but fat mass increased only in p62C (P < .05). Loss of skeletal muscle function was reported only in p62C (P < .05). Improved blood glucose levels and lower spleen mass were reported in RT and VRT compared to p62C (P < .05). However, the hindlimb muscle wet weights; myofiber cross-sectional area; and expression levels of the regulatory proteins for insulin signaling, inflammation, and muscle growth were not changed by any intervention. In conclusion, VitD administration attenuated the progression of obesity and preserved skeletal muscle function in p62-deficient mice. However, the obese mice improved systemic insulin sensitivity and inflammation only when the intervention involved RT.

The Evolving Applications of Creatine Supplementation: Could Creatine Improve Vascular Health?

Creatine is a naturally occurring compound, functioning in conjunction with creatine kinase to play a quintessential role in both cellular energy provision and intracellular energy shuttling. An extensive body of literature solidifies the plethora of ergogenic benefits gained following dietary creatine supplementation; however, recent findings have further indicated a potential therapeutic role for creatine in several pathologies such as myopathies, neurodegenerative disorders, metabolic disturbances, chronic kidney disease and inflammatory diseases. Furthermore, creatine has been found to exhibit non-energy-related properties, such as serving as a potential antioxidant and anti-inflammatory. Despite the therapeutic success of creatine supplementation in varying clinical populations, there is scarce information regarding the potential application of creatine for combatting the current leading cause of mortality, cardiovascular disease (CVD). Taking into consideration the broad ergogenic and non-energy-related actions of creatine, we hypothesize that creatine supplementation may be a potential therapeutic strategy for improving vascular health in at-risk populations such as older adults or those with CVD. With an extensive literature search, we have found only four clinical studies that have investigated the direct effect of creatine on vascular health and function. In this review, we aim to give a short background on the pleiotropic applications of creatine, and to then summarize the current literature surrounding creatine and vascular health. Furthermore, we discuss the varying mechanisms by which creatine could benefit vascular health and function, such as the impact of creatine supplementation upon inflammation and oxidative stress.

Vitamin D and Endothelial Function.

Vitamin D is known to elicit a vasoprotective effect, while vitamin D deficiency is a risk factor for endothelial dysfunction (ED). ED is characterized by reduced bioavailability of a potent endothelium-dependent vasodilator, nitric oxide (NO), and is an early event in the development of atherosclerosis. In endothelial cells, vitamin D regulates NO synthesis by mediating the activity of the endothelial NO synthase (eNOS). Under pathogenic conditions, the oxidative stress caused by excessive production of reactive oxygen species (ROS) facilitates NO degradation and suppresses NO synthesis, consequently reducing NO bioavailability. Vitamin D, however, counteracts the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase which produces ROS, and improves antioxidant capacity by enhancing the activity of antioxidative enzymes such as superoxide dismutase. In addition to ROS, proinflammatory mediators such as TNF-α and IL-6 are risk factors for ED, restraining NO and eNOS bioactivity and upregulating the expression of various atherosclerotic factors through the NF-κB pathway. These proinflammatory activities are inhibited by vitamin D by suppressing NF-κB signaling and production of proinflammatory cytokines. In this review, we discuss the diverse activities of vitamin D in regulating NO bioavailability and endothelial function.

Endothelial Dysfunction: Is There a Hyperglycemia-Induced Imbalance of NOX and NOS?

NADPH oxidases (NOX) are enzyme complexes that have received much attention as key molecules in the development of vascular dysfunction. NOX have the primary function of generating reactive oxygen species (ROS), and are considered the main source of ROS production in endothelial cells. The endothelium is a thin monolayer that lines the inner surface of blood vessels, acting as a secretory organ to maintain homeostasis of blood flow. The enzymatic production of nitric oxide (NO) by endothelial NO synthase (eNOS) is critical in mediating endothelial function, and oxidative stress can cause dysregulation of eNOS and endothelial dysfunction. Insulin is a stimulus for increases in blood flow and endothelium-dependent vasodilation. However, cardiovascular disease and type 2 diabetes are characterized by poor control of the endothelial cell redox environment, with a shift toward overproduction of ROS by NOX. Studies in models of type 2 diabetes demonstrate that aberrant NOX activation contributes to uncoupling of eNOS and endothelial dysfunction. It is well-established that endothelial dysfunction precedes the onset of cardiovascular disease, therefore NOX are important molecular links between type 2 diabetes and vascular complications. The aim of the current review is to describe the normal, healthy physiological mechanisms involved in endothelial function, and highlight the central role of NOX in mediating endothelial dysfunction when glucose homeostasis is impaired.

Resistance training during a 12-week protein supplemented VLCD treatment enhances weight-loss outcomes in obese patients.

BACKGROUND: This investigation evaluated the efficacy by which resistance training enhances body composition, metabolic, and functional outcomes for obese patients undergoing a 12-week medically supervised hypocaloric treatment. METHODS: This was a single-blind, randomized, parallel-group prospective trial. Morbidly obese patients were prescribed a 12-week proprietary very low calorie diet (VLCD) treatment (Optifast®) with supplemental protein (1120 kcals/day) and were placed in one of two groups for 14 weeks: 1) Standard Treatment Control (CON) (n = 5) or 2) Resistance Training (RT) (n = 6). Both groups underwent a pedometer-based walking program; however only RT performed resistance training 3 days/week for 12 weeks. Body composition, resting energy expenditure (REE), neuromuscular function, and serum biomarkers were measured at weeks 0, 6, and 13. RESULTS: Both groups exhibited a significant loss of total body mass (TBM) (CON: -19.4 ± 2.3 kg, p = 0.0009 vs. RT: -15.8 ± 1.5 kg, p = 0.0002) and fat mass (FM) (CON: -14.7 ± 1.8 kg, p = 0.0002 vs. RT: -15.1 ± 2.1 kg, p = 0.0002) with no group differences. CON lost 4.6 ± 0.8 kg (p = 0.004) of lean mass (LM) while RT demonstrated no changes. Group differences were found for the relative proportion of total weight-loss due to FM-loss (CON: 75.6 ± 3.4% vs. RT: 96.0 ± 6.0%, p = 0.03) and LM-loss (CON: 24.4 ± 3.2% vs. RT: 4.0 ± 6.5%, p = 0.03). CON demonstrated a 328.6 ± 72.7 kcal/day (-14.3 ± 2.4%) (p = 0.02) decrease in REE while RT exhibited a non-significant decrease of 4.6 ± 1.6% (p = 0.78). RT demonstrated greater improvements in all measures of contractile function and strength when compared to CON (p < 0.05). At post-treatment, RT exhibited greater serum free fatty acids (p = 0.01), glycerol (p = 0.003), and ß-hydroxybutyrate (p = 0.005) than CON. CONCLUSION: Resistance training was advantageous for weight-loss composition by preservation of LM without compromising overall weight- or fat-loss in morbidly obese men and women undergoing a protein supplemented VLCD. These changes accompanied positive adaptations for resting metabolism and muscular function.

Bone mineral density and content are differentially impacted by aerobic and resistance training in the colon-26 mouse model of cancer cachexia

Background: Cancer cachexia is a debilitating paraneoplastic syndrome featuring unintended weight loss and skeletal muscle atrophy. Evidence suggests that bone health may also be compromised, further limiting mobility and quality of life. Aerobic and resistance training was recently reported to differentially affect skeletal muscle adaptations in cancer cachectic mice. The purpose of this investigation was to assess the effects of aerobic and resistance training on bone mineral density (BMD) and bone mineral content (BMC) in mice with colon-26 (C26) tumor-induced cachexia. Methods: Twelve-month old Balb/c mice were aerobic-trained (wheel running 5 days/week) or resistance-trained (weighted ladder climbing 3days/week) for 8 weeks prior to C26 cell injection, followed by an additional three weeks of exercise. BMD and BMC were assessed pre- and post-training by dual-energy x-ray absorptiometry. Results: Resistance-trained C26 mice lost total BMD by 7% (p = 0.06), which did not occur in aerobic-trained C26 mice. In terms of pelvic bone, both resistance- and aerobic-trained C26 mice had significantly lower BMD values (−12%, p = 0.01 and −6%, p = 0.04, respectively), albeit to a lesser degree in aerobic-trained C26 mice. Furthermore, resistance-trained C26 mice tended to lose total BMC (−12%), whereas aerobic-trained C26 mice maintained total BMC. In mice without C26 tumors, resistance training significantly increased total BMD (+13%, p = 0.001). Conclusions: Aerobic and resistance training may differentially affect bone status in C26 cancer cachexia, with high resistance loading possibly being detrimental to total and pelvis BMD, a region expected to bear significant loading stress and contribute substantially to overall mobility. Because resistance training improved BMD in tumor-free mice, the C26 tumor burden appeared to impair the beneficial effect of resistance training on bone mass (AU)

Aerobic and resistance training dependent skeletal muscle plasticity in the colon-26 murine model of cancer cachexia.

PURPOSE: The appropriate mode of exercise training for cancer cachexia is not well-established. Using the colon-26 (C26) mouse model of cancer cachexia, we defined and compared the skeletal muscle responses to aerobic and resistance training. METHODS: Twelve-month old Balb/c mice were initially assigned to control, aerobic training (AT; wheel running), or resistance training (RT; ladder climbing) (n=16-17/group). After 8weeks of training, half of each group was injected with C26 tumor cells, followed by 3 additional weeks of training. Body composition and neuromuscular function was evaluated pre- and post-training. Muscles were collected post-training and analyzed for fiber cross-sectional area (CSA), Akt-mTOR signaling, and expression of insulin-like growth factor-I (IGF-I) and myogenic regulatory factors. RESULTS: Total body mass decreased (p<0.05) in C26 (-8%), AT+C26 (-18%), and RT+C26 (-15%) but not control. Sensorimotor function declined (p<0.05) in control (-16%), C26 (-13%), and RT+C26 (-23%) but not AT+C26. Similarly, strength/body weight decreased (p<0.05) in control (-7%), C26 (-21%), and RT+C26 (-10%) but not AT+C26. Gastrocnemius mass/body weight tended to be greater in AT+C26 vs. C26 (+6%, p=0.09). Enlargement of the spleen was partially corrected in AT+C26 (-27% vs. C26, p<0.05). Fiber CSA was lower in all C26 groups vs. control (-32% to 46%, p<0.05); however, the effect size calculated from C26 and AT+C26 was large (+24%, d=1.04). Phosphorylated levels of mTOR in AT+C26 exceeded C26 (+32%, p<0.05). RT+C26 showed greater mRNA expression (p<0.05) of IGF-IEa (+79%) and myogenin (+126%) with a strong tendency for greater IGF-IEb (+127%, p=0.069) vs. CONCLUSIONS: Aerobic or resistance training was unable to prevent tumor-induced body weight loss. However, aerobic training may have preserved function, reduced the inflammatory response of the spleen, and marginally rescued muscle mass possibly through activation of mTOR. Aerobic training may therefore have therapeutic value for patients with cancer cachexia. In contrast, resistance training induced the expression of genes associated with muscle damage and repair. This gene response may be supportive of excessive stress generated by high resistance loading in a tumor-bearing state.