Oral digoxin effects on exercise performance, K+ regulation and skeletal muscle Na+ ,K+ -ATPase in healthy humans.

We investigated whether digoxin lowered muscle Na+ ,K+ -ATPase (NKA), impaired muscle performance and exacerbated exercise K+ disturbances. Ten healthy adults ingested digoxin (0.25 mg; DIG) or placebo (CON) for 14 days and performed quadriceps strength and fatiguability, finger flexion (FF, 105%peak-workrate , 3 × 1 min, fourth bout to fatigue) and leg cycling (LC, 10 min at 33% V O 2 peak ${\rm{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{peak}}}$ and 67% V O 2 peak ${\rm{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{peak}}}$ , 90% V O 2 peak ${\rm{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{peak}}}$ to fatigue) trials using a double-blind, crossover, randomised, counter-balanced design. Arterial (a) and antecubital venous (v) blood was sampled (FF, LC) and muscle biopsied (LC, rest, 67% V O 2 peak ${\rm{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{peak}}}$ , fatigue, 3 h after exercise). In DIG, in resting muscle, [3 H]-ouabain binding site content (OB-Fab ) was unchanged; however, bound-digoxin removal with Digibind revealed total ouabain binding (OB+Fab ) increased (8.2%, P = 0.047), indicating 7.6% NKA-digoxin occupancy. Quadriceps muscle strength declined in DIG (-4.3%, P = 0.010) but fatiguability was unchanged. During LC, in DIG (main effects), time to fatigue and [K+ ]a were unchanged, whilst [K+ ]v was lower (P = 0.042) and [K+ ]a-v greater (P = 0.004) than in CON; with exercise (main effects), muscle OB-Fab was increased at 67% V O 2 peak ${\rm{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{peak}}}$ (per wet-weight, P = 0.005; per protein P = 0.001) and at fatigue (per protein, P = 0.003), whilst [K+ ]a , [K+ ]v and [K+ ]a-v were each increased at fatigue (P = 0.001). During FF, in DIG (main effects), time to fatigue, [K+ ]a , [K+ ]v and [K+ ]a-v were unchanged; with exercise (main effects), plasma [K+ ]a , [K+ ]v , [K+ ]a-v and muscle K+ efflux were all increased at fatigue (P = 0.001). Thus, muscle strength declined, but functional muscle NKA content was preserved during DIG, despite elevated plasma digoxin and muscle NKA-digoxin occupancy, with K+ disturbances and fatiguability unchanged. KEY POINTS: The Na+ ,K+ -ATPase (NKA) is vital in regulating skeletal muscle extracellular potassium concentration ([K+ ]), excitability and plasma [K+ ] and thereby also in modulating fatigue during intense contractions. NKA is inhibited by digoxin, which in cardiac patients lowers muscle functional NKA content ([3 H]-ouabain binding) and exacerbates K+ disturbances during exercise. In healthy adults, we found that digoxin at clinical levels surprisingly did not reduce functional muscle NKA content, whilst digoxin removal by Digibind antibody revealed an ∼8% increased muscle total NKA content. Accordingly, digoxin did not exacerbate arterial plasma [K+ ] disturbances or worsen fatigue during intense exercise, although quadriceps muscle strength was reduced. Thus, digoxin treatment in healthy participants elevated serum digoxin, but muscle functional NKA content was preserved, whilst K+ disturbances and fatigue with intense exercise were unchanged. This resilience to digoxin NKA inhibition is consistent with the importance of NKA in preserving K+ regulation and muscle function.

Hot water immersion; potential to improve intermittent running performance and perception of in-game running ability in semi-professional Australian Rules Footballers?

This study investigated whether hot water immersion (HWI) could heat acclimate athletes and improve intermittent running performance and perception of in-game running ability, during a competitive Australian Rules Football (ARF) season. Fifteen male semi-professional ARF athletes (Mean (SD); age: 22 (3) years, height: 182.3 (6.5) cm, mass: 80.5 (5.1) kg) completed either HWI (HEAT, N = 8, 13 (2) sessions, 322 (69) min exposure, 39.5 (0.3) °C) or acted as a control (CON, N = 7, no water immersion) over 6-weeks. Athletes completed a 30-15 Intermittent Fitness Test pre and post-intervention to assess intermittent running performance (VIFT), with perception of in-game running ability measured. Heat acclimation was determined via change in resting plasma volume, as well as physiological and perceptual responses during HWI. HEAT elicited large PV expansion (mean ± 90% CI: d = 1.03 ± 0.73), large decreases in heart rate (d = -0.89 ± 0.70), thermal sensation (d = -2.30 ± 1.15) and tympanic temperature (d = -1.18 ± 0.77). Large improvements in VIFT were seen in HEAT (d = 1.67 ± 0.93), with HEAT showing a greater improvement in VIFT when compared to CON (d = 0.81 ± 0.88). HEAT also showed greater belief that in-game running ability improved post-intervention (d = 2.15 ± 1.09) compared to CON. A 6-week HWI intervention can elicit heat acclimation, improve perception of in-game running ability, and potentially improve VIFT in semi-professional ARF athletes.

Plasma potassium concentration and cardiac repolarisation markers, Tpeak-Tend and Tpeak-Tend/QT, during and after exercise in healthy participants and in end-stage renal disease.

PURPOSE: The cardiac T-wave peak-to-end interval (Tpe) is thought to reflect dispersion in ventricular repolarisation, with abnormalities in Tpe associated with increased risk of arrhythmia. Extracellular K+ modulates cardiac repolarisation, and since arterial plasma K+ concentration ([K+]) rapidly increases during and declines following exercise, we investigated the relationship between [K+] and Tpe with exercise. METHODS: Serial ECGs (Tpe, Tpe/QT ratio) and [K+] were obtained from 8 healthy, normokalaemic volunteers and 22 patients with end-stage renal disease (ESRD), at rest, during, and after exhaustive exercise. RESULTS: Post-exercise [K+] nadir was 3.1 ± 0.1, 5.0 ± 0.2 and 4.0 ± 0.1 mmol.L-1 (mean ± SEM) for healthy participants and ESRD patients before and after haemodialysis, respectively. In healthy participants, compared to pre-exercise, recovery-induced low [K+] was associated with a prolongation of Tpe (110 ± 8 vs. 87 ± 5 ms, respectively, p = 0.03) and an increase in Tpe/QT ratio (0.28 ± 0.01 vs. 0.23 ± 0.01, respectively, p = 0.01). Analyses of serial data revealed [K+] as a predictor of Tpe in healthy participants (ß = -0.54 ±0.05, p < 0.0001), in ESRD patients (ß = -0.75 ± 0.06, p < 0.0001) and for all data pooled (ß = -0.61 ± 0.04, p < 0.0001). The [K+] was also a predictor of Tpe/QT ratio in healthy participants and ESRD patients. CONCLUSIONS: Tpe and Tpe/QT ratio are predicted by [K+] during exercise. Low [K+] during recovery from exercise was associated with increased Tpe and Tpe/QT, indicating accentuated dispersion of ventricular repolarisation. The findings suggest that variations in [K+] with physical exertion may unmask electrophysiological vulnerabilities to arrhythmia.

Metronomic 5-Fluorouracil Delivery Primes Skeletal Muscle for Myopathy but Does Not Cause Cachexia.

Skeletal myopathy encompasses both atrophy and dysfunction and is a prominent event in cancer and chemotherapy-induced cachexia. Here, we investigate the effects of a chemotherapeutic agent, 5-fluorouracil (5FU), on skeletal muscle mass and function, and whether small-molecule therapeutic candidate, BGP-15, could be protective against the chemotoxic challenge exerted by 5FU. Additionally, we explore the molecular signature of 5FU treatment. Male Balb/c mice received metronomic tri-weekly intraperitoneal delivery of 5FU (23 mg/kg), with and without BGP-15 (15 mg/kg), 6 times in total over a 15 day treatment period. We demonstrated that neither 5FU, nor 5FU combined with BGP-15, affected body composition indices, skeletal muscle mass or function. Adjuvant BGP-15 treatment did, however, prevent the 5FU-induced phosphorylation of p38 MAPK and p65 NF-B subunit, signalling pathways involved in cell stress and inflammatory signalling, respectively. This as associated with mitoprotection. 5FU reduced the expression of the key cytoskeletal proteins, desmin and dystrophin, which was not prevented by BGP-15. Combined, these data show that metronomic delivery of 5FU does not elicit physiological consequences to skeletal muscle mass and function but is implicit in priming skeletal muscle with a molecular signature for myopathy. BGP-15 has modest protective efficacy against the molecular changes induced by 5FU.

Post-exercise Cold Water Immersion Effects on Physiological Adaptations to Resistance Training and the Underlying Mechanisms in Skeletal Muscle: A Narrative Review.

Post-exercise cold-water immersion (CWI) is a popular recovery modality aimed at minimizing fatigue and hastening recovery following exercise. In this regard, CWI has been shown to be beneficial for accelerating post-exercise recovery of various parameters including muscle strength, muscle soreness, inflammation, muscle damage, and perceptions of fatigue. Improved recovery following an exercise session facilitated by CWI is thought to enhance the quality and training load of subsequent training sessions, thereby providing a greater training stimulus for long-term physiological adaptations. However, studies investigating the long-term effects of repeated post-exercise CWI instead suggest CWI may attenuate physiological adaptations to exercise training in a mode-specific manner. Specifically, there is evidence post-exercise CWI can attenuate improvements in physiological adaptations to resistance training, including aspects of maximal strength, power, and skeletal muscle hypertrophy, without negatively influencing endurance training adaptations. Several studies have investigated the effects of CWI on the molecular responses to resistance exercise in an attempt to identify the mechanisms by which CWI attenuates physiological adaptations to resistance training. Although evidence is limited, it appears that CWI attenuates the activation of anabolic signaling pathways and the increase in muscle protein synthesis following acute and chronic resistance exercise, which may mediate the negative effects of CWI on long-term resistance training adaptations. There are, however, a number of methodological factors that must be considered when interpreting evidence for the effects of post-exercise CWI on physiological adaptations to resistance training and the potential underlying mechanisms. This review outlines and critiques the available evidence on the effects of CWI on long-term resistance training adaptations and the underlying molecular mechanisms in skeletal muscle, and suggests potential directions for future research to further elucidate the effects of CWI on resistance training adaptations.

The Paradoxical Effect of PARP Inhibitor BGP-15 on Irinotecan-Induced Cachexia and Skeletal Muscle Dysfunction.

Chemotherapy-induced muscle wasting and dysfunction is a contributing factor to cachexia alongside cancer and increases the risk of morbidity and mortality. Here, we investigate the effects of the chemotherapeutic agent irinotecan (IRI) on skeletal muscle mass and function and whether BGP-15 (a poly-(ADP-ribose) polymerase-1 (PARP-1) inhibitor and heat shock protein co-inducer) adjuvant therapy could protect against IRI-induced skeletal myopathy. Healthy 6-week-old male Balb/C mice (n = 24; 8/group) were treated with six intraperitoneal injections of either vehicle, IRI (30 mg/kg) or BGP-15 adjuvant therapy (IRI+BGP; 15 mg/kg) over two weeks. IRI reduced lean and tibialis anterior mass, which were attenuated by IRI+BGP treatment. Remarkably, IRI reduced muscle protein synthesis, while IRI+BGP reduced protein synthesis further. These changes occurred in the absence of a change in crude markers of mammalian/mechanistic target of rapamycin (mTOR) Complex 1 (mTORC1) signaling and protein degradation. Interestingly, the cytoskeletal protein dystrophin was reduced in both IRI- and IRI+BGP-treated mice, while IRI+BGP treatment also decreased ß-dystroglycan, suggesting significant remodeling of the cytoskeleton. IRI reduced absolute force production of the soleus and extensor digitorum longus (EDL) muscles, while IRI+BGP rescued absolute force production of the soleus and strongly trended to rescue force output of the EDL (p = 0.06), which was associated with improvements in mass. During the fatiguing stimulation, IRI+BGP-treated EDL muscles were somewhat susceptible to rupture at the musculotendinous junction, likely due to BGP-15's capacity to maintain the rate of force development within a weakened environment characterized by significant structural remodeling. Our paradoxical data highlight that BGP-15 has some therapeutic advantage by attenuating IRI-induced skeletal myopathy; however, its effects on the remodeling of the cytoskeleton and extracellular matrix, which appear to make fast-twitch muscles more prone to tearing during contraction, could suggest the induction of muscular dystrophy and, thus, require further characterization.

Resistance training upregulates skeletal muscle Na+, K+-ATPase content, with elevations in both α1 and α2, but not ß isoforms.

PURPOSE: The Na+, K+-ATPase (NKA) is important in regulating trans-membrane ion gradients, cellular excitability and muscle function. We investigated the effects of resistance training in healthy young adults on the adaptability of NKA content and of the specific α and ß isoforms in human skeletal muscle. METHODS: Twenty-one healthy young males (22.9 ± 4.6 year; 1.80 ± 0.70 m, 85.1 ± 17.8 kg, mean ± SD) underwent 7 weeks of resistance training, training three times per week (RT, n = 16) or control (CON, n = 5). The training program was effective with a 39% gain in leg press muscle strength (p = 0.001). A resting vastus lateralis muscle biopsy was taken before and following RT or CON and assayed for NKA content ([3H]ouabain binding site content) and NKA isoform (α1, α2, ß1, ß2) abundances. RESULTS: After RT, each of NKA content (12%, 311 ± 76 vs 349 ± 76 pmol g wet weight-1, p = 0.01), NKA α1 (32%, p = 0.01) and α2 (10%, p < 0.01) isoforms were increased, whereas ß1 (p = 0.18) and ß2 (p = 0.22) isoforms were unchanged. NKA content and isoform abundances were unchanged during CON. CONCLUSIONS: Resistance training increased muscle NKA content through upregulation of both α1 and α2 isoforms, which were independent of ß isoform changes. In animal models, modulations in α1 and α2 isoform abundances in skeletal muscle may affect fatigue resistance during exercise, muscle hypertrophy and strength. Whether similar in-vivo functional benefits of these NKA isoform adaptations occurs in human muscle with resistance training remains to be determined.

Effects of repeated local heat therapy on skeletal muscle structure and function in humans.

The purpose of the present study was to examine the effects of repeated exposure to local heat therapy (HT) on skeletal muscle function, myofiber morphology, capillarization, and mitochondrial content in humans. Twelve young adults (23.6 ± 4.8 yr, body mass index 24.9 ± 3.0 kg/m2) had one randomly selected thigh treated with HT (garment perfused with water at ~52°C) for 8 consecutive weeks (90 min, 5 days/wk) while the opposite thigh served as a control. Biopsies were obtained from the vastus lateralis muscle before and after 4 and 8 wk of treatment. Knee extensor strength and fatigue resistance were also assessed using isokinetic dynamometry. The changes in peak isokinetic torque were higher (P = 0.007) in the thigh exposed to HT than in the control thigh at weeks 4 (control 4.2 ± 13.1 Nm vs. HT 9.1 ± 16.1 Nm) and 8 (control 1.8 ± 9.7 Nm vs. HT 7.8 ± 10.2 Nm). Exposure to HT averted a temporal decline in capillarization around type II fibers (P < 0.05), but had no effect on capillarization indexes in type I fibers. The content of endothelial nitric oxide synthase was ~18% and 35% higher in the thigh exposed to HT at 4 and 8 wk, respectively (P = 0.003). Similarly, HT increased the content of small heat shock proteins HSPB5 (P = 0.007) and HSPB1 (P = 0.009). There were no differences between thighs for the changes in fiber cross-sectional area and mitochondrial content. These results indicate that exposure to local HT for 8 wk promotes a proangiogenic environment and enhances muscle strength but does not affect mitochondrial content in humans.NEW & NOTEWORTHY We demonstrate that repeated application of heat therapy to the thigh with a garment perfused with warm water enhances the strength of knee extensors and influences muscle capillarization in parallel with increases in the content of endothelial nitric oxide synthase and small heat shock proteins. This practical method of passive heat stress may be a feasible tool to treat conditions associated with capillary rarefaction and muscle weakness.

Effects of testosterone suppression, hindlimb immobilization, and recovery on [3H]ouabain binding site content and Na+, K+-ATPase isoforms in rat soleus muscle.

We investigated the effects of testosterone suppression, hindlimb immobilization, and recovery on skeletal muscle Na+,K+-ATPase (NKA), measured via [3H]ouabain binding site content (OB) and NKA isoform abundances (α1-3, ß1-2). Male rats underwent castration or sham surgery plus 7 days of rest, 10 days of unilateral immobilization (cast), and 14 days of recovery, with soleus muscles obtained at each time from cast and noncast legs. Testosterone reduction did not modify OB or NKA isoforms in nonimmobilized control muscles. With sham surgery, OB was lower after immobilization in the cast leg than in both the noncast leg (-26%, P = 0.023) and the nonimmobilized control (-34%, P = 0.001), but OB subsequently recovered. With castration, OB was lower after immobilization in the cast leg than in the nonimmobilized control (-34%, P = 0.001), and remained depressed at recovery (-34%, P = 0.001). NKA isoforms did not differ after immobilization or recovery in the sham group. After castration, α2 in the cast leg was ~60% lower than in the noncast leg (P = 0.004) and nonimmobilized control (P = 0.004) and after recovery remained lower than the nonimmobilized control (-42%, P = 0.039). After immobilization, ß1 was lower in the cast than the noncast leg (-26%, P = 0.018), with ß2 lower in the cast leg than in the noncast leg (-71%, P = 0.004) and nonimmobilized control (-65%, P = 0.012). No differences existed for α1 or α3. Thus, both OB and α2 decreased after immobilization and recovery in the castration group, with α2, ß1, and ß2 isoform abundances decreased with immobilization compared with the sham group. Therefore, testosterone suppression in rats impaired restoration of immobilization-induced lowered number of functional NKA and α2 isoforms in soleus muscle.NEW & NOTEWORTHY: The Na+,K+-ATPase (NKA) is vital in muscle excitability and function. In rats, immobilization depressed soleus muscle NKA, with declines in [3H]ouabain binding, which was restored after 14 days recovery. After testosterone suppression by castration, immobilization depressed [3H]ouabain binding, depressed α2, ß1, and ß2 isoforms, and abolished subsequent recovery in [3H]ouabain binding and α2 isoforms. This may have implications for functional recovery for inactive men with lowered testosterone levels, such as in prostate cancer or aging.

Cold water immersion attenuates anabolic signaling and skeletal muscle fiber hypertrophy, but not strength gain, following whole-body resistance training.

We determined the effects of cold water immersion (CWI) on long-term adaptations and post-exercise molecular responses in skeletal muscle before and after resistance training. Sixteen men (22.9 ± 4.6 y; 85.1 ± 17.9 kg; mean ± SD) performed resistance training (3 day/wk) for 7 wk, with each session followed by either CWI [15 min at 10°C, CWI (COLD) group, n = 8] or passive recovery (15 min at 23°C, control group, n = 8). Exercise performance [one-repetition maximum (1-RM) leg press and bench press, countermovement jump, squat jump, and ballistic push-up], body composition (dual X-ray absorptiometry), and post-exercise (i.e., +1 and +48 h) molecular responses were assessed before and after training. Improvements in 1-RM leg press were similar between groups [130 ± 69 kg, pooled effect size (ES): 1.53 ± 90% confidence interval (CI) 0.49], whereas increases in type II muscle fiber cross-sectional area were attenuated with CWI (-1,959 ± 1,675 µM2 ; ES: -1.37 ± 0.99). Post-exercise mechanistic target of rapamycin complex 1 signaling (rps6 phosphorylation) was blunted for COLD at post-training (POST) +1 h (-0.4-fold, ES: -0.69 ± 0.86) and POST +48 h (-0.2-fold, ES: -1.33 ± 0.82), whereas basal protein degradation markers (FOX-O1 protein content) were increased (1.3-fold, ES: 2.17 ± 2.22). Training-induced increases in heat shock protein (HSP) 27 protein content were attenuated for COLD (-0.8-fold, ES: -0.94 ± 0.82), which also reduced total HSP72 protein content (-0.7-fold, ES: -0.79 ± 0.57). CWI blunted resistance training-induced muscle fiber hypertrophy, but not maximal strength, potentially via reduced skeletal muscle protein anabolism and increased catabolism. Post-exercise CWI should therefore be avoided if muscle hypertrophy is desired.NEW & NOTEWORTHY This study adds to existing evidence that post-exercise cold water immersion attenuates muscle fiber growth with resistance training, which is potentially mediated by attenuated post-exercise increases in markers of skeletal muscle anabolism coupled with increased catabolism and suggests that blunted muscle fiber growth with cold water immersion does not necessarily translate to impaired strength development.

Whey Protein Supplementation Post Resistance Exercise in Elderly Men Induces Changes in Muscle miRNA's Compared to Resistance Exercise Alone.

Progressive muscle loss with aging results in decreased physical function, frailty, and impaired metabolic health. Deficits in anabolic signaling contribute to an impaired ability for aged skeletal muscle to adapt in response to exercise and protein feeding. One potential contributing mechanism could be exerted by dysregulation of microRNAs (miRNAs). Therefore, the aim of this study was to determine if graded protein doses consumed after resistance exercise altered muscle miRNA expression in elderly men. Twenty-three senior men (67.9 ± 0.9 years) performed a bout of resistance exercise and were randomized to consume either a placebo, 20 or 40 g of whey protein (n = 8, n = 7, and n = 8, respectively). Vastus lateralis biopsies were collected before, 2 and 4 h after exercise. Expression of 19 miRNAs, previously identified to influence muscle phenotype, were measured via RT-PCR. Of these, miR-16-5p was altered with exercise in all groups (p = 0.032). Expression of miR-15a and-499a increased only in the placebo group 4 h after exercise and miR-451a expression increased following exercise only in the 40 g whey supplementation group. Changes in p-P70S6KThr389 and p-AktSer473 following exercise were correlated with alterations in miR-208a and-499a and-206 expression, irrespective of protein dose, suggesting a possible role for miRNA in the regulation of acute phosphorylation events during early hours of exercise recovery.

Co-treatment With BGP-15 Exacerbates 5-Fluorouracil-Induced Gastrointestinal Dysfunction.

Gastrointestinal (GI) side-effects of chemotherapy present a constant impediment to efficient and tolerable treatment of cancer. GI symptoms often lead to dose reduction, delays and cessation of treatment. Chemotherapy-induced nausea, bloating, vomiting, constipation, and/or diarrhea can persist up to 10 years post-treatment. We have previously reported that long-term 5-fluorouracil (5-FU) administration results in enteric neuronal loss, acute inflammation and intestinal dysfunction. In this study, we investigated whether the cytoprotectant, BGP-15, has a neuroprotective effect during 5-FU treatment. Balb/c mice received tri-weekly intraperitoneal 5-FU (23 mg/kg/d) administration with and without BGP-15 (15 mg/kg/d) for up to 14 days. GI transit was analyzed via in vivo serial X-ray imaging prior to and following 3, 7, and 14 days of treatment. On day 14, colons were collected for assessment of ex vivo colonic motility, neuronal mitochondrial superoxide, and cytochrome c levels as well as immunohistochemical analysis of myenteric neurons. BGP-15 did not inhibit 5-FU-induced neuronal loss, but significantly increased the number and proportion of choline acetyltransferase (ChAT)-immunoreactive (IR) and neuronal nitric oxide synthase (nNOS)-IR neurons in the myenteric plexus. BGP-15 co-administration significantly increased mitochondrial superoxide production, mitochondrial depolarization and cytochrome c release in myenteric plexus and exacerbated 5-FU-induced colonic inflammation. BGP-15 exacerbated 5-FU-induced colonic dysmotility by reducing the number and proportion of colonic migrating motor complexes and increasing the number and proportion of fragmented contractions and increased fecal water content indicative of diarrhea. Taken together, BGP-15 co-treatment aggravates 5-FU-induced GI side-effects, in contrast with our previous findings that BGP-15 alleviates GI side-effects of oxaliplatin.

Protection against severe hypokalemia but impaired cardiac repolarization after intense rowing exercise in healthy humans receiving salbutamol.

Intense exercise induces pronounced hyperkalemia, followed by transient hypokalemia in recovery. We investigated whether the ß2 agonist salbutamol attenuated the exercise hyperkalemia and exacerbated the postexercise hypokalemia, and whether hypokalemia was associated with impaired cardiac repolarization (QT hysteresis). Eleven healthy adults participated in a randomized, counterbalanced, double-blind trial receiving either 1,000 µg salbutamol (SAL) or placebo (PLAC) by inhalation. Arterial plasma potassium concentration ([K+]a) was measured at rest, during 3 min of intense rowing exercise, and during 60 min of recovery. QT hysteresis was calculated from ECG ( n = 8). [K+]a increased above baseline during exercise (rest, 3.72 ± 0.7 vs. end-exercise, 6.81 ± 1.4 mM, P < 0.001, mean ± SD) and decreased rapidly during early recovery to below baseline; restoration was incomplete at 60 min postexercise ( P < 0.05). [K+]a was less during SAL than PLAC (4.39 ± 0.13 vs. 4.73 ± 0.19 mM, pooled across all times, P = 0.001, treatment main effect). [K+]a was lower after SAL than PLAC, from 2 min preexercise until 2.5 min during exercise, and at 50 and 60 min postexercise ( P < 0.05). The postexercise decline in [K+]a was correlated with QT hysteresis ( r = 0.343, n = 112, pooled data, P = 0.001). Therefore, the decrease in [K+]a from end-exercise by ~4 mM was associated with reduced QT hysteresis by ~75 ms. Although salbutamol lowered [K+]a during exercise, no additive hypokalemic effects occurred in early recovery, suggesting there may be a protective mechanism against severe or prolonged hypokalemia after exercise when treated by salbutamol. This is important because postexercise hypokalemia impaired cardiac repolarization, which could potentially trigger arrhythmias and sudden cardiac death in susceptible individuals with preexisting hypokalemia and/or heart disease. NEW & NOTEWORTHY Intense rowing exercise induced a marked increase in arterial potassium, followed by a pronounced decline to hypokalemic levels. The ß2 agonist salbutamol lowered potassium during exercise and late recovery but not during early postexercise, suggesting a protective effect against severe hypokalemia. The decreased potassium in recovery was associated with impaired cardiac QT hysteresis, suggesting a link between postexercise potassium and the heart, with implications for increased risk of cardiac arrhythmias and, potentially, sudden cardiac death.

Oxaliplatin-induced enteric neuronal loss and intestinal dysfunction is prevented by co-treatment with BGP-15.

BACKGROUND AND PURPOSE: Gastrointestinal side effects of chemotherapy are an under-recognized clinical problem, leading to dose reduction, delays and cessation of treatment, presenting a constant challenge for efficient and tolerated anti-cancer treatment. We have found that oxaliplatin treatment results in intestinal dysfunction, oxidative stress and loss of enteric neurons. BGP-15 is a novel cytoprotective compound with potential HSP72 co-inducing and PARP inhibiting properties. In this study, we investigated the potential of BGP-15 to alleviate oxaliplatin-induced enteric neuropathy and intestinal dysfunction. EXPERIMENTAL APPROACH: Balb/c mice received oxaliplatin (3 mg·kg-1 ·day-1 ) with and without BGP-15 (15 mg·kg-1 ·day-1 : i.p.) tri-weekly for 14 days. Gastrointestinal transit was analysed via in vivo X-ray imaging, before and after treatment. Colons were collected to assess ex vivo motility, neuronal mitochondrial superoxide and cytochrome c levels and for immunohistochemical analysis of myenteric neurons. KEY RESULTS: Oxaliplatin-induced neuronal loss increased the proportion of neuronal NO synthase-immunoreactive neurons and increased levels of mitochondrial superoxide and cytochrome c in the myenteric plexus. These changes were correlated with an increase in PARP-2 immunoreactivity in the colonic mucosa and were attenuated by BGP-15 co-treatment. Significant delays in gastrointestinal transit, intestinal emptying and pellet formation, impaired colonic motor activity, reduced faecal water content and lack of weight gain associated with oxaliplatin treatment were restored to sham levels in mice co-treated with BGP-15. CONCLUSION AND IMPLICATIONS: Our results showed that BGP-15 ameliorated oxidative stress, increased enteric neuronal survival and alleviated oxaliplatin-induced intestinal dysfunction, suggesting that BGP-15 may relieve the gastrointestinal side effects of chemotherapy.

BGP-15 Protects against Oxaliplatin-Induced Skeletal Myopathy and Mitochondrial Reactive Oxygen Species Production in Mice.

Chemotherapy is a leading intervention against cancer. Albeit highly effective, chemotherapy has a multitude of deleterious side-effects including skeletal muscle wasting and fatigue, which considerably reduces patient quality of life and survivability. As such, a defense against chemotherapy-induced skeletal muscle dysfunction is required. Here we investigate the effects of oxaliplatin (OXA) treatment in mice on the skeletal muscle and mitochondria, and the capacity for the Poly ADP-ribose polymerase (PARP) inhibitor, BGP-15, to ameliorate any pathological side-effects induced by OXA. To do so, we investigated the effects of 2 weeks of OXA (3 mg/kg) treatment with and without BGP-15 (15 mg/kg). OXA induced a 15% (p < 0.05) reduction in lean tissue mass without significant changes in food consumption or energy expenditure. OXA treatment also altered the muscle architecture, increasing collagen deposition, neutral lipid and Ca2+ accumulation; all of which were ameliorated with BGP-15 adjunct therapy. Here, we are the first to show that OXA penetrates the mitochondria, and, as a possible consequence of this, increases mtROS production. These data correspond with reduced diameter of isolated FDB fibers and shift in the fiber size distribution frequency of TA to the left. There was a tendency for reduction in intramuscular protein content, albeit apparently not via Murf1 (atrophy)- or p62 (autophagy)- dependent pathways. BGP-15 adjunct therapy protected against increased ROS production and improved mitochondrial viability 4-fold and preserved fiber diameter and number. Our study highlights BGP-15 as a potential adjunct therapy to address chemotherapy-induced skeletal muscle and mitochondrial pathology.

Intense interval training in healthy older adults increases skeletal muscle [3H]ouabain-binding site content and elevates Na+,K+-ATPase α2 isoform abundance in Type II fibers.

Young adults typically adapt to intense exercise training with an increased skeletal muscle Na+,K+-ATPase (NKA) content, concomitant with reduced extracellular potassium concentration [K+] during exercise and enhanced exercise performance. Whether these changes with longitudinal training occur in older adults is unknown and was investigated here. Fifteen older adults (69.4 ± 3.5 years, mean ± SD) were randomized to either 12 weeks of intense interval training (4 × 4 min at 90-95% peak heart rate), 3 days/week (IIT, n = 8); or no exercise controls (n = 7). Before and after training, participants completed an incremental cycle ergometer exercise test until a rating of perceived exertion of 17 (very hard) on a 20-point scale was attained, with measures of antecubital venous [K+]v Participants underwent a resting muscle biopsy prior to and at 48-72 h following the final training session. After IIT, the peak exercise work rate (25%), oxygen uptake (16%) and heart rate (6%) were increased (P < 0.05). After IIT, the peak exercise plasma [K+]v tended to rise (P = 0.07), while the rise in plasma [K+]v relative to work performed (nmol.L-1J-1) was unchanged. Muscle NKA content increased by 11% after IIT (P < 0.05). Single fiber measurements, increased in NKA α2 isoform in Type II fibers after IIT (30%, P < 0.05), with no changes to the other isoforms in single fibers or homogenate. Thus, intense exercise training in older adults induced an upregulation of muscle NKA, with a fiber-specific increase in NKA α2 abundance in Type II fibers, coincident with increased muscle NKA content and enhanced exercise performance.

Preservation of skeletal muscle mitochondrial content in older adults: relationship between mitochondria, fibre type and high-intensity exercise training.

KEY POINTS: Ageing is associated with an upregulation of mitochondrial dynamics proteins mitofusin 2 (Mfn2) and mitochondrial dynamics protein 49 (MiD49) in human skeletal muscle with the increased abundance of Mfn2 being exclusive to type II muscle fibres. These changes occur despite a similar content of mitochondria, as measured by COXIV, NDUFA9 and complexes in their native states (Blue Native PAGE). Following 12 weeks of high-intensity training (HIT), older adults exhibit a robust increase in mitochondria content, while there is a decline in Mfn2 in type II fibres. We propose that the upregulation of Mfn2 and MiD49 with age may be a protective mechanism to protect against mitochondrial dysfunction, in particularly in type II skeletal muscle fibres, and that exercise may have a unique protective effect negating the need for an increased turnover of mitochondria. ABSTRACT: Mitochondrial dynamics proteins are critical for mitochondrial turnover and maintenance of mitochondrial health. High-intensity interval training (HIT) is a potent training modality shown to upregulate mitochondrial content in young adults but little is known about the effects of HIT on mitochondrial dynamics proteins in older adults. This study investigated the abundance of protein markers for mitochondrial dynamics and mitochondrial content in older adults compared to young adults. It also investigated the adaptability of mitochondria to 12 weeks of HIT in older adults. Both older and younger adults showed a higher abundance of mitochondrial respiratory chain subunits COXIV and NDUFA9 in type I compared with type II fibres, with no difference between the older adults and young groups. In whole muscle homogenates, older adults had higher mitofusin-2 (Mfn2) and mitochondrial dynamics protein 49 (MiD49) contents compared to the young group. Also, older adults had higher levels of Mfn2 in type II fibres compared with young adults. Following HIT in older adults, MiD49 and Mfn2 levels were not different in whole muscle and Mfn2 content decreased in type II fibres. Increases in citrate synthase activity (55%) and mitochondrial respiratory chain subunits COXIV (37%) and NDUFA9 (48%) and mitochondrial respiratory chain complexes (∼70-100%) were observed in homogenates and/or single fibres. These findings reveal (i) a similar amount of mitochondria in muscle from young and healthy older adults and (ii) a robust increase of mitochondrial content following 12 weeks of HIT exercise in older adults.

Cold-Water Immersion and Contrast Water Therapy: No Improvement of Short-Term Recovery After Resistance Training.

CONTEXT: An athlete's ability to recover quickly is important when there is limited time between training and competition. As such, recovery strategies are commonly used to expedite the recovery process. PURPOSE: To determine the effectiveness of both cold-water immersion (CWI) and contrast water therapy (CWT) compared with control on short-term recovery (<4 h) after a single full-body resistance-training session. METHODS: Thirteen men (age 26 ± 5 y, weight 79 ± 7 kg, height 177 ± 5 cm) were assessed for perceptual (fatigue and soreness) and performance measures (maximal voluntary isometric contraction [MVC] of the knee extensors, weighted and unweighted countermovement jumps) before and immediately after the training session. Subjects then completed 1 of three 14-min recovery strategies (CWI, CWT, or passive sitting [CON]), with the perceptual and performance measures reassessed immediately, 2 h, and 4 h postrecovery. RESULTS: Peak torque during MVC and jump performance were significantly decreased (P < .05) after the resistance-training session and remained depressed for at least 4 h postrecovery in all conditions. Neither CWI nor CWT had any effect on perceptual or performance measures over the 4-h recovery period. CONCLUSIONS: CWI and CWT did not improve short-term (<4-h) recovery after a conventional resistance-training session.

Heavy Resistance Training in Hypoxia Enhances 1RM Squat Performance.

Purpose: To determine if heavy resistance training in hypoxia (IHRT) is more effective at improving strength, power, and increasing lean mass than the same training in normoxia. Methods: A pair-matched, placebo-controlled study design included 20 resistance-trained participants assigned to IHRT (FIO2 0.143) or placebo (FIO2 0.20), (n = 10 per group). Participants were matched for strength and training. Both groups performed 20 sessions over 7 weeks either with IHRT or placebo. All participants were tested for 1RM, 20-m sprint, body composition, and countermovement jump pre-, mid-, and post-training and compared via magnitude-based inferences. Presentation of Results: Groups were not clearly different for any test at baseline. Training improved both absolute (IHRT: 13.1 ± 3.9%, effect size (ES) 0.60, placebo 9.8 ± 4.7%, ES 0.31) and relative 1RM (IHRT: 13.4 ± 5.1%, ES 0.76, placebo 9.7 ± 5.3%, ES 0.48) at mid. Similarly, at post both groups increased absolute (IHRT: 20.7 ± 7.6%, ES 0.74, placebo 14.1 ± 6.0%, ES 0.58) and relative 1RM (IHRT: 21.6 ± 8.5%, ES 1.08, placebo 13.2 ± 6.4%, ES 0.78). Importantly, the change in IHRT was greater than placebo at mid for both absolute [4.4% greater change, 90% Confidence Interval (CI) 1.0:8.0%, ES 0.21, and relative strength (5.6% greater change, 90% CI 1.0:9.4%, ES 0.31 (relative)]. There was also a greater change for IHRT at post for both absolute (7.0% greater change, 90% CI 1.3:13%, ES 0.33), and relative 1RM (9.2% greater change, 90% CI 1.6:14.9%, ES 0.49). Only IHRT increased countermovement jump peak power at Post (4.9%, ES 0.35), however the difference between IHRT and placebo was unclear (2.7, 90% CI -2.0:7.6%, ES 0.20) with no clear differences in speed or body composition throughout. Conclusion: Heavy resistance training in hypoxia is more effective than placebo for improving absolute and relative strength.

Dissociation between short-term unloading and resistance training effects on skeletal muscle Na+,K+-ATPase, muscle function, and fatigue in humans.

Physical training increases skeletal muscle Na+,K+-ATPase content (NKA) and improves exercise performance, but the effects of inactivity per se on NKA content and isoform abundance in human muscle are unknown. We investigated the effects of 23-day unilateral lower limb suspension (ULLS) and subsequent 4-wk resistance training (RT) on muscle function and NKA in 6 healthy adults, measuring quadriceps muscle peak torque; fatigue and venous [K+] during intense one-legged cycling exercise; and skeletal muscle NKA content ([3H]ouabain binding) and NKA isoform abundances (immunoblotting) in muscle homogenates (α1-3, ß1-2) and in single fibers (α1-3, ß1). In the unloaded leg after ULLS, quadriceps peak torque and cycling time to fatigue declined by 22 and 23%, respectively, which were restored with RT. Whole muscle NKA content and homogenate NKA α1-3 and ß1-2 isoform abundances were unchanged with ULLS or RT. However, in single muscle fibers, NKA α3 in type I (-66%, P = 0.006) and ß1 in type II fibers (-40%, P = 0.016) decreased after ULLS, with other NKA isoforms unchanged. After RT, NKA α1 (79%, P = 0.004) and ß1 (35%, P = 0.01) increased in type II fibers, while α2 (76%, P = 0.028) and α3 (142%, P = 0.004) increased in type I fibers compared with post-ULLS. Despite considerably impaired muscle function and earlier fatigue onset, muscle NKA content and homogenate α1 and α2 abundances were unchanged, thus being resilient to inactivity induced by ULLS. Nonetheless, fiber type-specific downregulation with inactivity and upregulation with RT of several NKA isoforms indicate complex regulation of muscle NKA expression in humans.