Ammonium Chloride Ingestion Attenuates Exercise-Induced mRNA Levels in Human Muscle.

Minimizing the decrease in intracellular pH during high-intensity exercise training promotes greater improvements in mitochondrial respiration. This raises the intriguing hypothesis that pH may affect the exercise-induced transcription of genes that regulate mitochondrial biogenesis. Eight males performed 10x2-min cycle intervals at 80% VO2speak intensity on two occasions separated by ~2 weeks. Participants ingested either ammonium chloride (ACID) or calcium carbonate (PLA) the day before and on the day of the exercise trial in a randomized, counterbalanced order, using a crossover design. Biopsies were taken from the vastus lateralis muscle before and after exercise. The mRNA level of peroxisome proliferator-activated receptor co-activator 1α (PGC-1α), citrate synthase, cytochome c and FOXO1 was elevated at rest following ACID (P<0.05). During the PLA condition, the mRNA content of mitochondrial- and glucose-regulating proteins was elevated immediately following exercise (P<0.05). In the early phase (0-2 h) of post-exercise recovery during ACID, PGC-1α, citrate synthase, cytochome C, FOXO1, GLUT4, and HKII mRNA levels were not different from resting levels (P>0.05); the difference in PGC-1α mRNA content 2 h post-exercise between ACID and PLA was not significant (P = 0.08). Thus, metabolic acidosis abolished the early post-exercise increase of PGC-1α mRNA and the mRNA of downstream mitochondrial and glucose-regulating proteins. These findings indicate that metabolic acidosis may affect mitochondrial biogenesis, with divergent responses in resting and post-exercise skeletal muscle.

Multi-omic integrated networks connect DNA methylation and miRNA with skeletal muscle plasticity to chronic exercise in Type 2 diabetic obesity.

Epigenomic regulation of the transcriptome by DNA methylation and posttranscriptional gene silencing by miRNAs are potential environmental modulators of skeletal muscle plasticity to chronic exercise in healthy and diseased populations. We utilized transcriptome networks to connect exercise-induced differential methylation and miRNA with functional skeletal muscle plasticity. Biopsies of the vastus lateralis were collected from middle-aged Polynesian men and women with morbid obesity (44 kg/m(2) ± 10) and Type 2 diabetes before and following 16 wk of resistance (n = 9) or endurance training (n = 8). Longitudinal transcriptome, methylome, and microRNA (miRNA) responses were obtained via microarray, filtered by novel effect-size based false discovery rate probe selection preceding bioinformatic interrogation. Metabolic and microvascular transcriptome topology dominated the network landscape following endurance exercise. Lipid and glucose metabolism modules were connected to: microRNA (miR)-29a; promoter region hypomethylation of nuclear receptor factor (NRF1) and fatty acid transporter (SLC27A4), and hypermethylation of fatty acid synthase, and to exon hypomethylation of 6-phosphofructo-2-kinase and Ser/Thr protein kinase. Directional change in the endurance networks was validated by lower intramyocellular lipid, increased capillarity, GLUT4, hexokinase, and mitochondrial enzyme activity and proteome. Resistance training also lowered lipid and increased enzyme activity and caused GLUT4 promoter hypomethylation; however, training was inconsequential to GLUT4, capillarity, and metabolic transcriptome. miR-195 connected to negative regulation of vascular development. To conclude, integrated molecular network modelling revealed differential DNA methylation and miRNA expression changes occur in skeletal muscle in response to chronic exercise training that are most pronounced with endurance training and topographically associated with functional metabolic and microvascular plasticity relevant to diabetes rehabilitation.

Unaccustomed eccentric contractions impair plasma K+ regulation in the absence of changes in muscle Na+,K+-ATPase content.

The Na+,K+-ATPase (NKA) plays a fundamental role in the regulation of skeletal muscle membrane Na+ and K+ gradients, excitability and fatigue during repeated intense contractions. Many studies have investigated the effects of acute concentric exercise on K+ regulation and skeletal muscle NKA, but almost nothing is known about the effects of repeated eccentric contractions. We therefore investigated the effects of unaccustomed maximal eccentric knee extensor contractions on K+ regulation during exercise, peak knee extensor muscle torque, and vastus lateralis muscle NKA content and 3-O-MFPase activity. Torque measurements, muscle biopsies, and venous blood samples were taken before, during and up to 7 days following the contractions in six healthy adults. Eccentric contractions reduced peak isometric muscle torque immediately post-exercise by 26±11% and serum creatine kinase concentration peaked 24 h post-exercise at 339±90 IU/L. During eccentric contractions, plasma [K+] rose during Set 1 and remained elevated at ∼4.9 mM during sets 4-10; this was despite a decline in work output by Set 4, which fell by 18.9% at set 10. The rise in plasma [K+] x work(-1) ratio was elevated over Set 2 from Set 4- Set 10. Eccentric contractions had no effect on muscle NKA content or maximal in-vitro 3-O-MFPase activity immediately post- or up to 7 d post-exercise. The sustained elevation in plasma [K+] despite a decrease in work performed by the knee extensor muscles suggests an impairment in K+ regulation during maximal eccentric contractions, possibly due to increased plasma membrane permeability or to excitation-contraction uncoupling.

High-Protein Diets and Renal Disease : is there a Relationship in People with Type 2 Diabetes? : Review

Diabetic kidney disease is the greatest cause of kidney disease worldwide and a cause of significant morbidity and mortality - in New Zealand it accounts for more than 50 of patients receiving renal dialysis. Diet and lifestyle modification are recognised as the cornerstones of management of type 2 diabetes. Dietary interventions to aid weight loss and improve glycaemic control typically increase total energy intake from protein by about 10. The effects of increased protein intake on kidney function and progression of kidney disease in type 2 diabetes has not been established. Evaluation of the literature reviewed here suggests that there is some evidence for the benefit of treating existing nephropathy with protein restriction; but no evidence that increasing protein intake in patients with microalbuminuria accelerates diabetic nephropathy; or causes it in those with normal renal function. Substituting chicken; fish and vegetable protein sources for red meat may be helpful; while retaining a focus on other aspects of a healthy diet; such as high fibre; will ensure that potential risks are minimised

Exercise improves quality of life in indigenous Polynesian peoples with type 2 diabetes and visceral obesity.

BACKGROUND: To evaluate the differential effect of 2, group-based exercise modalities on quality of life (QoL) in indigenous Polynesian peoples with type 2 diabetes (T2DM) and visceral obesity. METHODS: Participants were randomized to resistance training or aerobic training performed 3 times per for 16 weeks. The Short-Form 36 was administered at baseline and post intervention to assess 8 domains and physical and mental component scales (PCS and MCS) of QoL. RESULTS: With the exception of Mental Health and MCS, all scores were lower at baseline than general population norms. Significant improvements were documented in several QoL scores in each group post intervention. No group x time interactions were noted. Pooled analyses of the total cohort indicated significantly improved Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Role-Emotional, PCS and MCS. Adaptation ranged from 5%-22%, and demonstrated a moderate-to-large effect (Cohen's d = 0.64-1.29). All measures of QoL increased to near equivalent, or greater than general norms. CONCLUSION: Exercise, regardless of specific modality, can improve many aspects of QoL in this population. Robust trials are required to investigate factors mediating improvements in QoL, and create greater advocacy for exercise as a QoL intervention in this and other indigenous populations with T2DM.

Exercise intervention in New Zealand Polynesian peoples with type 2 diabetes: Cultural considerations and clinical trial recommendations.

The Maori and Pacific Islands peoples of New Zealand suffer a greater burden of type 2 diabetes mellitus (T2DM) and associated comorbidities than their European counterparts. Empirical evidence supports the clinical application of aerobic and resistance training for effective diabetes management and potential remission, but few studies have investigated the effectiveness of these interventions in specific ethnic cohorts. We recently conducted the first trial to investigate the effect of prescribed exercise training in Polynesian people with T2DM. This article presents the cultural considerations undertaken to successfully implement the study. The research procedures were accepted and approved by cultural liaisons and potential participants. The approved methodology involved a trial evaluating and comparing the effects of two, 16-week exercise regimens (i.e. aerobic training and resistance training) on glycosylated haemoglobin (HbA1c), related diabetes markers (i.e. insulin resistance, blood lipids, relevant cytokines and anthropometric and hemodynamic indices) and health-related quality of life. Future exercise-related research or implementation strategies in this cohort should focus on cultural awareness and techniques to enhance participation and compliance. Our approach to cultural consultation could be considered by researchers undertaking trials in this and other ethnic populations suffering an extreme burden of T2DM, including indigenous Australians and Americans.

Mortality in dialysis patients may not be associated with ESA dose: a 2-year prospective observational study.

BACKGROUND: Anaemia of chronic kidney disease increases the risk of death and adverse events, but can be managed using erythropoiesis stimulating agents (ESAs). However, recent evidence suggests that targeting a higher haemoglobin concentration ([Hb]) increases mortality risk, and both higher [Hb] targets and ESA doses have been implicated. Nonetheless, a causative role has not been demonstrated, and this potential relationship requires further appraisal in such a complex patient group. METHODS: The relationship between the haematopoietic response to ESAs and patient survival in 302 stable, prevalent dialysis patients was explored in a prospective, single-centre study. Clinical and laboratory parameters influencing mortality and ESA resistance were analysed. Patients were stratified into 5 groups, according to their [Hb] and ESA dosage, and were followed for 2 years. RESULTS: Little difference in co-morbidities between groups was identified. 73 patients died and 36 were transplanted. Initial analysis suggested a direct relationship between mortality and ESA dosage. However, Cox proportional hazards multivariate analysis demonstrated mortality risk was associated only with age (adjusted HR per year: 1.061, 95% CI 1.031-1.092), dialysis duration (adjusted HR: 1.010, 95% CI 1.004-1.016), peripheral vascular disease (adjusted HR: 1.967, 95% CI 1.083-3.576) and CRP (adjusted HR: 1.024, 95% CI 1.011-1.039). Mortality was increased in patients poorly responsive to ESAs (55.5%). CONCLUSION: ESA dose does not appear to contribute substantially to mortality risk in dialysis patients. Instead, age and co-morbidities appear to be the critical determinants. A poor response to ESAs is a marker of overall poor health status.

South Pacific Islanders resist type 2 diabetes: comparison of aerobic and resistance training.

The purpose of this study was to evaluate the effectiveness of two exercise modalities for improving glycosylated hemoglobin (HbA1c) and associated clinical outcomes in Polynesian adults diagnosed with type 2 diabetes and visceral obesity. Twenty-six adults were randomized to receive resistance training or aerobic training, 3×/week, for 16 weeks. Dependent variables collected before and after intervention included: diabetes markers including HbA1c, blood lipids, relevant cytokines (C-reactive protein, adiponectin), and anthropometric and hemodynamic indices. Eighteen participants (72% female; age: 49.3 ± 5.3 years; waist circumference: 128.7 ± 18.7 cm) completed the intervention and follow-up assessments. Body mass index in the whole cohort at baseline indicated Class III (morbid) obesity (43.8 ± 9.5 kg/m(2)). Compliance to training was 73 ± 19 and 67 ± 18% in the aerobic and resistance training groups, respectively. HbA1c remained elevated in both groups after training. Aerobic training reduced systolic and diastolic blood pressure and increased serum triglycerides (all P < 0.05). No other exercise-induced adaptations were noted within or between groups. Post hoc analysis using pooled data indicated that higher adherence to training (≥75% attendance, n = 8) significantly reduced waist circumference (P < 0.001) and tended to reduce body weight and fasting insulin (all P ≤ 0.11) versus lower adherence (<75% attendance, n = 10). In conclusion, this study did not demonstrate an improvement in HbA1c with exercise in morbidly obese Polynesian people. Future investigations involving exercise regimens that are more practicable and which involve greater frequency and duration of training may be required to induce significant and clinically meaningful adaptations in this unique diabetes population.

Impaired exercise performance and muscle Na(+),K(+)-pump activity in renal transplantation and haemodialysis patients.

BACKGROUND: We examined whether abnormal skeletal muscle Na(+),K(+)-pumps underlie impaired exercise performance in haemodialysis patients (HDP) and whether these are improved in renal transplant recipients (RTx). METHODS: Peak oxygen consumption ( O(2peak)) and plasma [K(+)] were measured during incremental exercise in 9RTx, 10 HDP and 10 healthy controls (CON). Quadriceps peak torque (PT), fatigability (decline in strength during thirty contractions), thigh muscle cross-sectional area (TMCSA) and vastus lateralis Na(+),K(+)-pump maximal activity, content and isoform (α(1)-α(3), ß(1)-ß(3)) abundance were measured. RESULTS: O(2peak) was 32 and 35% lower in RTx and HDP than CON, respectively (P < 0.05). PT was less in RTx and HDP than CON (P < 0.05) but did not differ when expressed relative to TMCSA. Fatigability was ∼1.6-fold higher in RTx (24 ± 11%) and HDP (25 ± 4%) than CON (15 ± 5%, P < 0.05). Na(+),K(+)-pump activity was 28 and 31% lower in RTx and HDP, respectively than CON (P < 0.02), whereas content and isoform abundance did not differ. Pooled (n = 28) O(2peak) correlated with Na(+),K(+)-pump activity (r = 0.45, P = 0.02). CONCLUSIONS: O(2peak) and muscle Na(+),K(+)-pump activity were depressed and muscle fatigability increased in HDP, with no difference observed in RTx. These findings are consistent with the possibility that impaired exercise performance in HDP and RTx may be partially due to depressed muscle Na(+),K(+)-pump activity and relative TMCSA.

Encapsulating peritoneal sclerosis--a complication of peritoneal dialysis.

Encapsulating peritoneal sclerosis (EPS) is a rare complication of peritoneal dialysis. It often presents with non-specific symptoms, leading to a delay in diagnosis and a poor prognosis. Here we report a case of EPS in a patient treated with peritoneal dialysis and discuss the risk factors, diagnostic challenges and treatment options available.

Effects of endurance training on extrarenal potassium regulation and exercise performance in patients on haemodialysis.

BACKGROUND: Haemodialysis patients (HDP) with anaemia display impaired plasma K(+) regulation during exercise and poor exercise performance. Epoetin treatment and exercise training improve exercise performance in HDP, but whether this is associated with improved K(+) regulation is unknown. METHODS: Six HDP with near-normal [Hb] were tested for aerobic power ( ) and plasma [K(+)] during incremental exercise; quadriceps muscle strength (peak torque, PT) from 0 to 360 degrees s(-1) and fatiguability (decline in strength during thirty contractions). Tests were conducted at baseline, after 6 weeks of normal activity (pre-train) and following 6 weeks cycle training (post-train). Six healthy untrained controls (CON) matched for age, sex, mass and height were tested at baseline. RESULTS: In HDP at baseline, and PT from 0 to 360 degrees s(-1) were respectively reduced by 37% and 27-42%, compared to CON (P < 0.05). Plasma [K(+)], the rise in [K(+)] (Delta[K(+)]) and the Delta[K(+)] relative to total work done (Delta[K(+)] work(-1) ratio) during incremental exercise were all higher in HDP at baseline compared to CON (P < 0.05). Exercise training increased time to fatigue by 12% (P < 0.05) but did not improve K(+) regulation or . An inverse correlation was found between the Delta[K(+)] work(-1) ratio and for pooled CON and HDP data. CONCLUSIONS: In HDP treated with epoetin, poor exercise performance was related to impaired extrarenal K(+) regulation, whilst training improved exercise performance but not K(+) regulation. Thus, although impaired extrarenal K(+) regulation may contribute to poor exercise performance in HDP, exercise performance can still improve with training despite unchanged K(+) regulation.

Calpain-3 is autolyzed and hence activated in human skeletal muscle 24 h following a single bout of eccentric exercise.

The function and normal regulation of calpain-3, a muscle-specific Ca(2+)-dependent protease, is uncertain, although its absence leads to limb-girdle muscular dystrophy type 2A. This study examined the effect of eccentric exercise on calpain-3 autolytic activation, because such exercise is known to damage sarcomeric structures and to trigger adaptive changes that help prevent such damage on subsequent exercise. Six healthy human subjects performed a 30-min bout of one-legged, eccentric, knee extensor exercise. Torque measurements, vastus lateralis muscle biopsies, and venous blood samples were taken before and up to 7 days following the exercise. Peak isometric muscle torque was depressed immediately and at 3 h postexercise and recovered by 24 h, and serum creatine kinase concentration peaked at 24 h postexercise. The amount of autolyzed calpain-3 was unchanged immediately and 3 h after exercise, but increased markedly (from approximately 16% to approximately 35% of total) 24 h after the exercise, and returned to preexercise levels within 7 days. In contrast, the eccentric exercise produced little autolytic activation of the ubiquitous Ca(2+)-activated protease, mu-calpain. Eccentric exercise is the first physiological circumstance shown to result in calpain-3 activation in vivo.

Exercise performance falls over time in patients with chronic kidney disease despite maintenance of hemoglobin concentration.

Physical function is limited in patients with kidney disease, although previous studies have been confounded by anemia. What is not clear is how physical performance changes over time as renal function deteriorates. A cohort of 12 patients (10 male, two female; mean +/- SD age 49 +/- 11 yr) who had stages 3 to 4 chronic kidney disease without previous anemia were examined, and nine were followed for a 2-yr period. Assessments were made of peak oxygen consumption (VO2peak) by cycle ergometry, leg extension strength, and fatigue on an isokinetic dynamometer and thigh muscle cross-sectional area (TMCSA) by computed tomography. At baseline, creatinine clearance was 31 +/- 13 ml/min and hemoglobin concentration ([Hb]) was 129 +/- 9 g/L. VO2peak was low (1.88 L/min, 82% of predicted), and maximal isometric voluntary contraction was 188 +/- 42 Nm, with a TMCSA of 144 +/- 27 cm2. VO2peak correlated with creatinine clearance corrected for body surface area (r = 0.613, P = 0.034) but not to [Hb]. VO2peak adjusted for patient weight correlated with leg fatigue (r = -0.693, P = 0.012). For those with follow-up tests, there were falls in renal function by 28% (P = 0.007) and VO2peak by 9% (P = 0.03), whereas [Hb] did not change. Leg strength fell across a range of isokinetic speeds (P = 0.04), whereas no change in TMCSA was observed. In conclusion, exercise performance as measured by aerobic (VO2peak) and leg strength tests were reduced in patients with stages 3 to 4 chronic kidney disease. As renal function declined over time, there was a corresponding decline in exercise performance even when [Hb] was maintained.

Impact of statin treatment on 1-year functional and histologic renal allograft outcome.

BACKGROUND: Statins are antilipidemic agents that exhibit a variety of cellular effects independent of their lipid-lowering action. A retrospective study was undertaken to establish the impact of statins on graft outcome in the first year posttransplantation. METHODS: Data from patients with uniform immunosuppression (cyclosporine, mycophenolate mofetil, and prednisolone) who underwent transplantation at the authors' unit from 1997 to 2002 were reviewed. Patients prescribed statins were compared with those not on a statin. Mean change in creatinine clearance (CrCl) from 3 to 12 months posttransplantation was calculated. Histomorphometric analysis was used to quantify fractional interstitial area and collagen III deposition in matched preperfusion and 12-month protocol biopsy specimens. RESULTS: Seventy-seven patients met study criteria: statin, n=44 patients; nonstatin, n=33 patients. Median time to commencing a statin was 5 weeks. At 3 months, CrCl (+/-SEM) was similar: 51.6+/-2.9 mL/min (statin) versus 51.3+/-1 mL/min (nonstatin). At 12 months, the mean change in CrCl was 4.1+/-1 mL/min (statin) compared with -2.0+/-1.8 mL/min (nonstatin), resulting in a difference of 6.13 mL/min at 12 months (P<0.005). Mean preperfusion fractional interstitial areas were similar (23.9+/-1.6%; P=not significant [NS]). On 12-month biopsy specimens, the fractional interstitial area had increased to 34+/-3.2% in the nonstatin group (P<0.005), with no change in the statin group. Interstitial collagen III deposition was similar in preperfusion biopsy specimens (10.4+/-1%; P=NS), but at 12 months it was significantly greater in the nonstatin group (17.6+/-1%; P<0.05) CONCLUSIONS: Early introduction of statins may be associated with improved 1-year graft outcome.

Haemoglobin response to subcutaneous versus intravenous epoetin alfa administration in iron-replete haemodialysis patients.

BACKGROUND: Numerous prior studies have reported that a substantially higher dose of epoetin is required to maintain haemoglobin (Hb) concentration when patients are switched from a subcutaneous (s.c.) to intravenous (i.v.) route of administration. Many of the reported trials, however, involved patients who did not have adequate serum iron levels. It was hypothesized that patients with adequate iron stores who are switched from one route of administration to the other without a change in dose will experience substantially less change in their Hb concentration. METHODS: Haemodialysis patients who were iron replete (ferritin 300-800 microg/L, transferrin saturation (TSAT) 25-50%) participated in a prospective, randomized cross-over trial receiving epoetin for 3 months either by s.c. or i.v. injection followed by a further 3 months of epoetin via the other route. The principal aim was to determine changes in Hb concentration without altering the weekly epoetin dose. The secondary aim was to assess whether the frequency of dosing (once, twice or thrice weekly) influenced the Hb concentration response. RESULTS: Eighty-one patients (mean age 62 years, 60% male) entered the study and 15 withdrew prior to study completion. Forty-three patients began s.c. epoetin alfa administration (group A) and 38 on i.v. (group B). Median ferritin and TSAT at entry for groups A and B were 409 and 394 microg/L (NS) and 31 and 32% (NS), respectively, which remained within the target range during the study. Median epoetin doses for groups A and B were similar (90 vs 93 IU/kg per week, NS). After 3 months, the mean Hb concentration rose for group A (SC; 118.7-121.9 g/L (P = 0.03)) but it fell for group B (i.v.; 119.1-116.0 g/L (P = 0.019)). Following the change in route of administration, the Hb concentration for group A (i.v.) fell by 5.1% over 3 months (121.9-115.4, P < 0.001) and rose by 2.8% for group B (s.c.) over 3 months (116.0-119.7, P = 0.001). Similar significant changes in the Hb concentration were seen at different dosing frequencies. CONCLUSION: Subcutaneous administration of epoetin produces a significant, although slight clinical change in Hb concentration compared with i.v. administration in stable, iron replete, haemodialysis patients. A similar effect appears to prevail regardless of the frequency of injections given.

Acute renal failure associated with Legionella pneumonia and acute cholecystitis.

BACKGROUND AND AIMS: Acute cholecystitis in critically ill patients has a high morbidity and mortality. We observed a number of patients presenting with Legionella pneumonia and acute renal failure who subsequently developed acute cholecystitis. There has previously been no reported association between Legionella pneumonia, renal failure and cholecystitis, prompting this examination of the cases and review of the available literature. METHODS: The Western Hospital patient record discharge codes (DRG) from 1993 to 2001 were searched retrospectively for all cases of Legionella pneumonia or acute renal failure requiring dialysis (ARF) at presentation or during their period of hospitalization. Acute cholecystitis was then included as a cross-search and results analysed. RESULTS: Twenty-six cases of isolated Legionella pneumonia and 112 of ARF were identified with a further 10 having both conditions simultaneously. Of these 10 cases, three were identified as also having acute cholecystitis. The combination of Legionella pneumonia and ARF was associated with an increased risk of acute cholecystitis (P = 0.002) whereas neither condition in isolation demonstrated this association. CONCLUSIONS: Patients with Legionella pneumonia can become critically ill with multiple complications including acute renal failure requiring dialysis. In this setting, they may have an increased risk of developing acute cholecystitis, which clinically can be difficult to ascertain. Diagnosis requires a high index of suspicion and vigilance.