A pilot randomized trial of conventional versus advanced pelvic floor exercises to treat urinary incontinence after radical prostatectomy: a study protocol.

BACKGROUND: Radical prostatectomy is the most common and effective treatment for localized prostate cancer. Unfortunately, radical prostatectomy is associated with urinary incontinence and has a significant negative impact on quality of life. Pelvic floor exercises are the most common non-invasive management strategy for urinary incontinence following radical prostatectomy; however, studies provide inconsistent findings regarding their efficacy. One potential reason for sub-optimal efficacy of these interventions is the under-utilization of regional muscles that normally co-activate with the pelvic floor, such as the transverse abdominis, rectus abdominis, and the diaphragm. Two novel approaches to improve urinary continence recovery are 'Pfilates' and 'Hypopressives' that combine traditional pelvic floor exercises with the activation of additional supportive muscles. Our study will compare an advanced pelvic floor exercise training program that includes Pfilates and Hypopressives, to a conventional pelvic floor exercises regimen for the treatment of post-radical prostatectomy urinary incontinence. METHODS/DESIGN: This is a pilot, randomized controlled trial of advanced pelvic floor muscle training versus conventional pelvic floor exercises for men with localized prostate cancer undergoing radical prostatectomy. Eighty-eight men who will be undergoing radical prostatectomy at hospitals in Toronto, Canada will be recruited. Eligible participants must not have undergone androgen deprivation therapy and/or radiation therapy. Participants will be randomized 1:1 to receive 26 weeks of the advanced or conventional pelvic floor exercise programs. Each program will be progressive and have comparable exercise volume. The primary outcomes are related to feasibility for a large, adequately powered randomized controlled trial to determine efficacy for the treatment of urinary incontinence. Feasibility will be assessed via recruitment success, participant retention, outcome capture, intervention adherence, and prevalence of adverse events. Secondary outcomes of intervention efficacy include measures of pelvic floor strength, urinary incontinence, erectile function, and quality of life. Secondary outcome measures will be collected prior to surgery (baseline), and at 2, 6, 12, 26-weeks post-operatively. DISCUSSION: Pfilates and Hypopressives are novel approaches to optimizing urinary function after radical prostatectomy. This trial will provide the foundation of data for future, large-scale trials to definitively describe the effect of these advanced pelvic floor exercise modalities compared to conventional pelvic floor exercise regimes for men with prostate cancer undergoing radical prostatectomy TRIAL REGISTRATION: Clinicalstrials.gov Identifier: NCT02233608.

Functional capacity and heart rate response: associations with nocturnal hypertension.

BACKGROUND: Absences of normative, 10-20 % declines in blood pressure (BP) at night, termed nocturnal non-dipping, are linked to increased cardiovascular mortality risks. Current literature has linked these absences to psychological states, hormonal imbalance, and disorders involving hyper-arousal. This study focuses on evaluating associations between nocturnal non-dipping and indices of functional cardiac capacity and fitness. METHODS: The current study was a cross-sectional evaluation of the associations between physical capacity variables e.g. Metabolic Equivalent (MET) and Maximum Heart Rate (MHR), Heart rate reserve (HRR), and degree of reduction in nocturnal systolic blood pressure (SBP) or diastolic blood pressure (DBP), also known as 'dipping'. The study sample included 96 cardiac patient participants assessed for physical capacity and ambulatory blood pressure monitoring. In addition to evaluating differences between groups on nocturnal BP 'dipping', physical capacity, diagnoses, and medications, linear regression analyses were used to evaluate potential associations between nocturnal SBP and DBP 'dipping', and physical capacity indices. RESULTS: 45 males and 14 females or 61.5 % of 96 consented participants met criteria as non-dippers (<10 % drop in nocturnal BP). Although non-dippers were older (p = .01) and had a lower maximum heart rate during the Bruce stress test (p = .05), dipping was only significantly associated with Type 2 Diabetes co-morbidity and was not associated with type of medication. Within separate linear regression models controlling for participant sex, MHR (ß = 0.26, p = .01, R(2) = .06), HRR (ß = 0. 19, p = .05, R(2) = .05), and METs (ß = 0.21, p = .04, R(2) = .04) emerged as significant but small predictors of degree of nighttime SBP dipping. Similar relationships were not observed for DBP. CONCLUSIONS: Since the variables reflecting basic heart function and fitness (MHR and METs), did not account for appreciable variances in nighttime BP, nocturnal hypertension appears to be a complex, multi-faceted phenomena.

Fatty acid transport proteins chronically relocate to the transverse-tubules in muscle from obese Zucker rats but are resistant to further insulin-induced translocation.

OBJECTIVES: Recently, we have demonstrated that FA transport proteins are located within the t-tubule fraction of rodent muscle, and that insulin stimulation causes their translocation to this membrane fraction. Chronic relocation of the FA transport protein FAT/CD36 to the sarcolemma is observed in obese rodents and humans, and correlates with intramuscular lipid accumulation and insulin resistance. It is not known whether in an obese, insulin resistant state FA transporters also chronically relocate to the t-tubules. Furthermore, it is not known whether the insulin-stimulated translocation of the various FA transport proteins to the t-tubules is impaired in insulin resistance. METHODS: Sarcolemmal and t-tubule membrane fractions were isolated via differential centrifugation from muscles of lean and obese female Zucker rats during basal or insulin stimulated conditions. FA transport proteins were measured via western blot on both membrane fractions. RESULTS: Our results demonstrate that in muscle from insulin resistant Zucker rats, FAT/CD36, FABPpm and FATP1 are all increased on the t-tubules in the basal state (+72%, +120%, and +69%, respectively), potentially contributing to the accumulation of intramuscular lipids. Insulin failed to increase the content of the FA transport proteins on either the t-tubule or sarcolemma above the elevated basal levels, analogous to the well characterized impairment of insulin-stimulated GLUT4 translocation to both membrane domains in obesity. CONCLUSION: FA transport proteins chronically relocate to the t-tubule domain in insulin resistant muscle, potentially contributing to lipid accumulation. Further translocation of the FA transport proteins to this domain during insulin stimulation, however, is impaired.

Insulin and contraction-induced movement of fatty acid transport proteins to skeletal muscle transverse-tubules is distinctly different than to the sarcolemma.

Fatty acid (FA) transport proteins are known to exist on the sarcolemma of skeletal muscle. However, it is unknown whether the t-tubules, which comprise ~60% of the cell surface, also harbor these proteins. We examined FA transport proteins from both membrane fractions in unstimulated, insulin-stimulated and contracted skeletal muscle. Sarcolemmal and t-tubule membrane fractions were isolated from the same muscle homogenate using a discontinuous sucrose gradient. Our results demonstrate that the relative content of FA transport proteins within the two fractions and the magnitude to which they increase when stimulated were distinctly different. In unstimulated muscle FAT/CD36, FATP4, and FABPpm are abundant on the sarcolemma (3-, 8-, and 10-fold greater than t-tubule, respectively), whereas FATP1 resides primarily within the t-tubule fraction (1- to 2-fold greater than the sarcolemma). With both stimuli, in terms of absolute increase, FAT/CD36 predominantly translocated to the sarcolemma and FATP1 to the t-tubules. There are clear differences in the profile of FA transport proteins and the response to stimuli of the sarcolemma and t-tubules. FATP1, a variable and unresponsive protein on the sarcolemma, appears to reside primarily in the t-tubules where it is responsive to stimuli.

Effects of age and pathology on stance modifications in response to increased postural threat.

This study investigated modifications to standing posture in response to elevated postural anxiety evoked by a potential physical threat to stability. Sixteen young adults, 16 older adults and 16 patients diagnosed with Parkinson's disease (PD) stood with or without the expectation of a threat to their posture (i.e., external trunk perturbation). This method allowed for the assessment of the effects of anticipatory anxiety on standing posture associated with an ecologically valid and direct threat to stability. Our manipulation was successful as all participants, independent of age and disease, reported significant increases in postural anxiety when anticipating a threat to their posture. The trunk sway modifications observed in response to elevated postural anxiety were dependent on age and disease. Young adults showed increased trunk sway in both pitch and roll directions while older adults demonstrated decreased trunk sway but only in the roll direction when standing and expecting a threat to posture compared to standing without this threat. Individuals with PD showed no significant changes in trunk pitch or roll sway when anticipating a threat to posture compared to standing without this threat. Our findings suggest that the effects of postural anxiety on postural control are dependent on the context associated with the postural threat, and age and disease status.

Recovered insulin response by 2 weeks of leptin administration in high-fat fed rats is associated with restored AS160 activation and decreased reactive lipid accumulation.

Leptin is an adipokine that increases fatty acid (FA) oxidation, decreases intramuscular lipid stores, and improves insulin response in skeletal muscle. In an attempt to elucidate the underlying mechanisms by which these metabolic changes occur, we administered leptin (Lep) or saline (Sal) by miniosmotic pumps to rats during the final 2 wk of a 6-wk low-fat (LF) or high-fat (HF) diet. Insulin-stimulated glucose transport was impaired by the HF diet (HF-Sal) but was restored with leptin administration (HF-Lep). This improvement was associated with restored phosphorylation of Akt and AS160 and decreased in reactive lipid species (ceramide, diacylglycerol), known inhibitors of the insulin-signaling cascade. Total muscle citrate synthase (CS) activity was increased by both leptin and HF diet, but was not additive. Leptin increased subsarcolemmal (SS) and intramyofibrillar (IMF) mitochondria CS activity. Total muscle, sarcolemmal, and mitochondrial (SS and IMF) FA transporter (FAT/CD36) protein content was significantly increased with the HF diet, but not altered by leptin. Therefore, the decrease in reactive lipid stores and subsequent improvement in insulin response, secondary to leptin administration in rats fed a HF diet was not due to a decrease in FA transport protein content or altered cellular distribution.

Restoration of skeletal muscle leptin response does not precede the exercise-induced recovery of insulin-stimulated glucose uptake in high-fat-fed rats.

Leptin administration increases fatty acid (FA) oxidation rates and decreases lipid storage in oxidative skeletal muscle, thereby improving insulin response. We have previously shown high-fat (HF) diets to rapidly induce skeletal muscle leptin resistance, prior to the disruption of normal muscle FA metabolism (increase in FA transport; accumulation of triacylglycerol, diacylglycerol, ceramide) that occurs in advance of impaired insulin signaling and glucose transport. All of this occurs within a 4-wk period. Conversely, exercise can rapidly improve insulin response, in as little as one exercise bout. Thus, if the early development of leptin resistance is a contributor to HF diet-induced insulin resistance (IR) in skeletal muscle, then it is logical to predict that the rapid restoration of insulin response by exercise training would be preceded by the recovery of leptin response. In the current study, we sought to determine 1) whether 1, 2, or 4 wk of exercise training was sufficient to restore leptin response in isolated soleus muscle of rats already consuming a HF diet (60% kcal), and 2) whether this preceded the training-induced corrections in FA metabolism and improved insulin-stimulated glucose transport. In the low-fat (LF)-fed control group, insulin increased glucose transport by 153% and leptin increased AMPK and ACC phosphorylation and the rate of palmitate oxidation (+73%). These responses to insulin and leptin were either severely blunted or absent following 4 wk of HF feeding. Exercise intervention decreased muscle ceramide content (-28%) and restored insulin-stimulated glucose transport to control levels within 1 wk; muscle leptin response (AMPK and ACC phosphorylation, FA oxidation) was also restored, but not until the 2-wk time point. In conclusion, endurance exercise training is able to restore leptin response, but this does not appear to be a necessary precursor for the restoration of insulin response.

Oral administration of a PPAR-delta agonist to rodents worsens, not improves, maximal insulin-stimulated glucose transport in skeletal muscle of different fibers.

Agonists targeting the nuclear receptor peroxisome proliferator-activated receptors (PPAR)-delta may be potential therapeutic agents for insulin-resistant related conditions, as they may be able to stimulate fatty acid (FA) oxidation and attenuate the accumulation of harmful lipid species in skeletal muscle. Several reports have demonstrated that PPAR-delta agonists improve whole body insulin sensitivity. However, whether these agonists exert their direct effects on glucose and FA metabolism in skeletal muscle, and specifically with different fiber types, is unknown. This study was undertaken to determine the effects of oral treatment with the PPAR-delta agonist, GW 501516, in conjunction with the administration of a high-saturated-fat diet on insulin-stimulated glucose transport in isolated oxidative (soleus) and glycolytic (epitrochlearis) rodent skeletal muscle in vitro. High-fat feeding significantly decreased maximal insulin-stimulated glucose transport in soleus, but not epitrochlearis muscle, and was associated with increased skeletal muscle diacylglycerol and ceramide content. Unexpectedly, treatment with the PPAR-delta agonist significantly reduced insulin-stimulated glucose transport in both soleus and epitrochlearis muscles, regardless of dietary fat content. The reduction in insulin-stimulated glucose transport induced by the agonist was associated with large increases in total muscle fatty acid translocase (FAT)/CD36protein content, but not diacylglycerol or ceramide contents. Agonist treatment did not alter the protein content of PPAR-delta, GLUT4, or insulin-signaling proteins (IRS-1, p85 PI3-K, Akt). Agonist treatment led to a small, but significant increase, in the oxidative capacity of glycolytic but not oxidative muscle. We propose that chronic treatment with the PPAR-delta agonist GW 501516 may induce or worsen insulin resistance in rodent skeletal muscle by increasing the capacity for FA transport across the sarcolemma without a sufficient compensatory increase in FA oxidation. However, an accumulation of diacylglycerol and ceramide, while associated with diet-induced insulin resistance, does not appear to be responsible for the agonist-induced reduction in insulin-stimulated glucose transport.

The interaction between adipokines, diet and exercise on muscle insulin sensitivity.

PURPOSE OF REVIEW: High-fat diets lead to obesity and increase the risk of developing insulin resistance and type 2 diabetes. Adipose tissue and skeletal muscle act as endocrine organs, and produce various cytokines that can potentially alter peripheral insulin sensitivity. The purpose of the present review is to briefly summarize the effects of major cytokines (leptin, adiponectin, tumor necrosis factor-alpha, and interleukin-6) on muscle metabolism and insulin response, with a focus on the effects of diet and exercise. RECENT FINDINGS: Leptin and adiponectin improve insulin sensitivity. However, in obesity there is a diminished response to these adipokines. This resistance can be induced very rapidly and may lead to subsequent impairments in insulin response. Tumor necrosis factor-alpha is a proinflammatory cytokine that has been implicated as a mediator of insulin resistance, particularly in obesity. Interleukin-6 was the first identified myokine. There is evidence to implicate interleukin-6 both as a mediator of impaired insulin action in obesity, and also as a facilitator of increased fuel metabolism during exercise. The effect of each of these cytokines on muscle insulin sensitivity can be modulated by diet and exercise. SUMMARY: Much of the information summarized in the present review focuses on the effects of various cytokines in isolation, although in vivo there can be considerable interaction with each other. Future research should consider these potential interactions.

Skeletal muscle type comparison of subsarcolemmal mitochondrial membrane phospholipid fatty acid composition in rat.

The phospholipid composition of membranes can influence the physiological functioning of the cell or subcellular organelle. This association has been previously demonstrated in skeletal muscle, where cellular or subcellular membrane, specifically mitochondria, phospholipid composition is linked to muscle function. However, these observations are based on whole mixed skeletal muscle analysis, with little information on skeletal muscles of differing fiber-type compositions. These past approaches that used mixed muscle may have misidentified outcomes or masked differences. Thus, the purpose of this study was to compare the phospholipid fatty acid composition of subsarcolemmal (SS) mitochondria isolated from slow-twitch postural (soleus), fast-twitch highly oxidative glycolytic locomotory (red gastrocnemius), and fast-twitch oxidative glycolytic locomotory (plantaris) skeletal muscles. The main findings of the study demonstrated unique differences between SS mitochondrial membranes from postural soleus compared to the other locomotory skeletal muscles examined, specifically lower percentage mole fraction of phosphatidylcholine (PC) and significantly higher percentage mole fraction of saturated fatty acids (SFA) and lower n6 polyunsaturated fatty acids (PUFA), resulting in a lower unsaturation index. We also found that although there was no difference in the percentage mole fraction of cardiolipin (CL) between skeletal muscle types examined, CL of soleus mitochondrial membranes were approximately twofold more SFA and approximately two-thirds less PUFA, resulting in a 20-30% lower unsaturation and peroxidation indices. Thus, the results of this study indicate unique membrane lipid composition of mitochondria isolated from different skeletal muscle types, a potential consequence of their respective duty cycles.