Highlighting the idea of exerkines in the management of cancer patients with cachexia: novel insights and a critical review.

BACKGROUND: Exerkines are all peptides, metabolites, and nucleic acids released into the bloodstream during and after physical exercise. Exerkines liberated from skeletal muscle (myokines), the heart (cardiokines), liver (hepatokines), white adipose tissue (adipokines), brown adipose tissue (batokines), and neurons (neurokines) may benefit health and wellbeing. Cancer-related cachexia is a highly prevalent disorder characterized by weight loss with specific skeletal muscle and adipose tissue loss. Many studies have sought to provide exercise strategies for managing cachexia, focusing on musculoskeletal tissue changes. Therefore, understanding the responses of musculoskeletal and other tissue exerkines to acute and chronic exercise may provide novel insight and recommendations for physical training to counteract cancer-related cachexia. METHODS: For the purpose of conducting this study review, we made efforts to gather relevant studies and thoroughly discuss them to create a comprehensive overview. To achieve this, we conducted searches using appropriate keywords in various databases. Studies that were deemed irrelevant to the current research, not available in English, or lacking full-text access were excluded. Nevertheless, it is important to acknowledge the limited amount of research conducted in this specific field. RESULTS: In order to obtain a comprehensive understanding of the findings, we prioritized human studies in order to obtain results that closely align with the scope of the present study. However, in instances where human studies were limited or additional analysis was required to draw more robust conclusions, we also incorporated animal studies. Finally, 295 studies, discussed in this review. CONCLUSION: Our understanding of the underlying physiological mechanisms related to the significance of investigating exerkines in cancer cachexia is currently quite basic. Nonetheless, this demonstrated that resistance and aerobic exercise can contribute to the reduction and control of the disease in individuals with cancer cachexia, as well as in survivors, by inducing changes in exerkines.

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.

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.

Methods to match high-intensity interval exercise intensity in hypoxia and normoxia - A pilot study.

The aim of this study was to compare high-intensity interval exercise (HIIE) sessions prescribed on the basis of a maximal value (peak power output, PPO) and a submaximal value (lactate threshold, LT) derived from graded exercise tests (GXTs) in normoxia and hypoxia. METHODS: A total of ten males (aged 18-37) volunteered to participate in this study. The experimental protocol consisted of a familiarization procedure, two GXTs under normoxia (FiO2 = 0.209) and two GXTs under normobaric hypoxia (FiO2 = 0.140), and three HIIE sessions performed in a random order. The HIIE sessions included one at hypoxia (HY) and two at normoxia (one matched for the absolute intensity in hypoxia, designated as NA, and one matched for the relative intensity in hypoxia, designated as NR). RESULTS: The data demonstrated that there was significant lower peak oxygen uptake (V̇O2peak), peak heart rate (HRpeak), PPO, and LT derived from GXTs in hypoxia, with higher respiratory exchange ratio (RER), when compared to those from GXTs performed in normoxia (p < 0.001). Among the three HIIE sessions, the NA session resulted in lower percentage of HRpeak (85.0 ± 7.5% vs 94.4 ± 5.0%; p = 0.002) and V̇O2peak (74.1 ± 9.1% vs 88.7 ± 7.7%; p = 0.005), when compared to the NR session. HIIE sessions in HY and NR resulted in similar percentage of HRpeak and V̇O2peak, as well as similar rating of perceived exertion and RER. The blood lactate level increased immediately after all the three HIIE sessions (p < 0.001), while higher blood lactate concentrations were observed immediately after the HY (p = 0.0003) and NR (p = 0.014) sessions when compared with NA. CONCLUSION: Combining of PPO and LT derived from GXTs can be used to prescribe exercise intensity of HIIE in hypoxia.

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.

High-intensity interval training in chronic kidney disease: A randomized pilot study.

INTRODUCTION: High-intensity interval training (HIIT) increases mitochondrial biogenesis and cardiorespiratory fitness in chronic disease populations, however has not been studied in people with chronic kidney disease (CKD). The aim of this study was to compare the feasibility, safety, and efficacy of HIIT with moderate-intensity continuous training (MICT) in people with CKD. METHODS: Fourteen individuals with stage 3-4 CKD were randomized to 3 supervised sessions/wk for 12 weeks, of HIIT (n = 9, 4 × 4 minute intervals, 80%-95% peak heart rate [PHR]) or MICT (n = 5, 40 minutes, 65% PHR). Feasibility was assessed via session attendance and adherence to the exercise intensity. Safety was examined by adverse event reporting. Efficacy was determined from changes in cardiorespiratory fitness (VO2 peak), exercise capacity (METs), and markers of mitochondrial biogenesis (PGC1α protein levels), muscle protein catabolism (MuRF1), and muscle protein synthesis (p-P70S6k Thr389 ). RESULTS: Participants completed a similar number of sessions in each group (HIIT = 33.0[7.0] vs MICT = 33.5[3.3] sessions), and participants adhered to the target heart rates. There were no adverse events attributable to exercise training. There was a significant time effect for exercise capacity (HIIT = +0.8 ± 1.2; MICT = +1.3 ± 1.6 METs; P = 0.01) and muscle protein synthesis (HIIT = +0.6 ± 1.1; MICT = +1.4 ± 1.7 au; P = 0.04). However, there were no significant (P > 0.05) group × time effects for any outcomes. CONCLUSION: This pilot study demonstrated that HIIT is a feasible and safe option for people with CKD, and there were similar benefits of HIIT and MICT on exercise capacity and skeletal muscle protein synthesis. These data support a larger trial to further evaluate the effectiveness of HIIT.

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 following sprint interval training does not alter endurance signaling pathways or training adaptations in human skeletal muscle.

We investigated the underlying molecular mechanisms by which postexercise cold-water immersion (CWI) may alter key markers of mitochondrial biogenesis following both a single session and 6 wk of sprint interval training (SIT). Nineteen men performed a single SIT session, followed by one of two 15-min recovery conditions: cold-water immersion (10°C) or a passive room temperature control (23°C). Sixteen of these participants also completed 6 wk of SIT, each session followed immediately by their designated recovery condition. Four muscle biopsies were obtained in total, three during the single SIT session (preexercise, postrecovery, and 3 h postrecovery) and one 48 h after the last SIT session. After a single SIT session, phosphorylated (p-)AMPK, p-p38 MAPK, p-p53, and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) mRNA were all increased (P < 0.05). Postexercise CWI had no effect on these responses. Consistent with the lack of a response after a single session, regular postexercise CWI had no effect on PGC-1α or p53 protein content. Six weeks of SIT increased peak aerobic power, maximal oxygen consumption, maximal uncoupled respiration (complexes I and II), and 2-km time trial performance (P < 0.05). However, regular CWI had no effect on changes in these markers, consistent with the lack of response in the markers of mitochondrial biogenesis. Although these observations suggest that CWI is not detrimental to endurance adaptations following 6 wk of SIT, they question whether postexercise CWI is an effective strategy to promote mitochondrial biogenesis and improvements in endurance performance.

Salbutamol effects on systemic potassium dynamics during and following intense continuous and intermittent exercise.

PURPOSE: Salbutamol inhalation is permissible by WADA in athletic competition for asthma management and affects potassium regulation, which is vital for muscle function. Salbutamol effects on arterial potassium concentration ([K+]a) during and after high-intensity continuous exercise (HIcont) and intermittent exercise comprising repeated, brief sprints (HIint), and on performance during HIint are unknown and were investigated. METHODS: Seven recreationally active men participated in a double-blind, randomised, cross-over design, inhaling 1000 µg salbutamol or placebo. Participants cycled continuously for 5 min at 40 % [Formula: see text]O2peak and 60 % [Formula: see text]O2peak, then HIcont (90 s at 130 % [Formula: see text]O2peak), 20 min recovery, and then HIint (3 sets, 5 × 4 s sprints), with 30 min recovery. RESULTS: Plasma [K+]a increased throughout exercise and subsequently declined below baseline (P < 0.001). Plasma [K+]a was greater during HIcont than HIint (P < 0.001, HIcont 5.94 ± 0.65 vs HIint set 1, 4.71 ± 0.40 mM); the change in [K+]a from baseline (Δ[K+]a) was 2.6-fold greater during HIcont than HIint (P < 0.001). The Δ[K+] throughout the trial was less with salbutamol than placebo (P < 0.001, treatment main effect, 0.03 ± 0.67 vs 0.22 ± 0.69 mM, respectively); and remained less after correction for fluid shifts (P < 0.001). The Δ[K+] during HIcont was less after salbutamol (P < 0.05), but not during HIint. Blood lactate, plasma pH, and the work output during HIint did not differ between trials. CONCLUSIONS: Inhaled salbutamol modulated the [K+]a rise across the trial, comprising intense continuous and intermittent exercise and recovery, lowering Δ[K+] during HIcont. The limited [K+]a changes during HIint suggest that salbutamol is unlikely to influence systemic [K+] during periods of intense effort in intermittent sports.

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.

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.

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.

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.

Validity and relevance of the pack hike wildland firefighter work capacity test: a review.

Fighting wildland fire is a physically demanding occupation. Wildland firefighters need to be physically fit to work safely and productively. To determine whether personnel are fit for duty, many firefighting agencies employ physical competency tests, such as the pack hike test (PHT). The PHT involves a 4.83-km hike over level terrain carrying a 20.4-kg pack within a 45-min period. The PHT was devised to test the job readiness of US wildland firefighters but is also currently used by some fire agencies in Australia and Canada. This review discusses the history and development of the PHT with emphasis on the process of test validation. Research-based training advice for the PHT is given, as well as discussion of the risks associated with completing the PHT. Different versions and modifications to the PHT have emerged in recent years and these are discussed with regard to their validity. Finally, this review addresses the relevance and validity of the PHT for Australian and Canadian wildland firefighters. STATEMENT OF RELEVANCE: This paper reviews the history, development and validity of the PHT, an internationally recognised and utilised wildland firefighter work capacity test. It is concluded that while the PHT has general content validity for US wildland firefighters, verification of its reliability, criterion and construct validity is still needed.

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.

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.

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 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.

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.

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.