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% VO2peak${\rm{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{peak}}}$ and 67% VO2peak${\rm{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{peak}}}$, 90% VO2peak${\rm{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{peak}}}$ 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% VO2peak${\rm{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{peak}}}$, fatigue, 3 h after exercise). In DIG, in resting muscle, 3H‐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% VO2peak${\rm{V}}_{{{\rm{O}}}_{\rm{2}}{\rm{peak}}}$ (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 (3H‐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.
figure legend Digoxin specifically inhibits Na,K‐pumps in all tissues and in skeletal muscle, and thus could therefore impair cellular Na/K homeostasis, excitability and contractility. In heart failure patients, digoxin binds to and therefore reduces the Na,K‐pump content in skeletal muscle; this lower number of available functional Na,K‐pumps is consistent with an elevated circulating K during exercise. We show here in healthy volunteers that oral digoxin intake, which resulted in therapeutic digoxin, did not reduce the muscle Na,K‐pump content, which was unchanged. However, measures with digibind revealed the total number of Na,K‐pumps was elevated by 8%. Digoxin did not affect either arterial K or time to fatigue, during both finger flexion exercise and leg cycling exercise. This indicates a remarkable preservation of skeletal muscle Na,K‐pumps and thus also of circulating K and performance during fatiguing, intense exercise challenges. However, one adverse consequence of digoxin was a 4% reduction in muscle strength.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Limb immobilization results in a rapid loss of muscle size and strength. The resultant alterations in signaling pathways governing myogenesis, catabolism, and mitochondrial biogenesis are likely to ...include posttranscriptional regulation mediated by altered microRNAs (miRNAs). Given that protein ingestion exerts an anabolic action and may act as a countermeasure to mitigate muscle loss with immobilization, it is important to examine miRNA in this context. The objective of the study is therefore to characterize the vastus lateralis miRNA response to 14 days of disuse in males (45–60 years) randomized to receive supplementation with 20 g d−1 of dairy protein (n = 12) or isocaloric carbohydrate placebo (n = 13). Biopsies are collected before and after a 2‐week immobilization period. Of the 24 miRNAs previously identified in myogenic regulation, seven (miR‐133a, −206, −15a, −451a, −126, −208b, and let‐7e) are increased with immobilization irrespective of group; five (miR‐16, −494, let‐7a, −7c, and 7d) increased only in the carbohydrate group; and eight (miR‐1, −486, −23a, −23b, −26a, −148b, let‐7b, and −7g) are divergently expressed between groups (suppressed with protein). The ability of protein supplementation to differentially regulate miRNAs involved in key muscle regulatory pathways following short‐term limb immobilization reflects potential protective function in mitigating muscle loss during limb immobilization.
Lower‐limb immobilization in middle‐aged men alters intramuscular microRNA profiles, reflecting signaling pathways regulate muscle fiber type, myogenesis, oxidative capacity, and apoptosis. Dairy protein supplementation attenuated disuse induces increases in 13 microRNAs. A 20 g dose of dairy protein ingested daily during disuse results in a microRNA profile that may reflect the maintenance of muscle metabolism.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
During the Millennium Development Goal (MDG) era, many countries in Africa achieved marked reductions in under-5 and neonatal mortality. Yet the pace of progress toward these goals substantially ...varied at the national level, demonstrating an essential need for tracking even more local trends in child mortality. With the adoption of the Sustainable Development Goals (SDGs) in 2015, which established ambitious targets for improving child survival by 2030, optimal intervention planning and targeting will require understanding of trends and rates of progress at a higher spatial resolution. In this study, we aimed to generate high-resolution estimates of under-5 and neonatal all-cause mortality across 46 countries in Africa.
We assembled 235 geographically resolved household survey and census data sources on child deaths to produce estimates of under-5 and neonatal mortality at a resolution of 5 × 5 km grid cells across 46 African countries for 2000, 2005, 2010, and 2015. We used a Bayesian geostatistical analytical framework to generate these estimates, and implemented predictive validity tests. In addition to reporting 5 × 5 km estimates, we also aggregated results obtained from these estimates into three different levels—national, and subnational administrative levels 1 and 2—to provide the full range of geospatial resolution that local, national, and global decision makers might require.
Amid improving child survival in Africa, there was substantial heterogeneity in absolute levels of under-5 and neonatal mortality in 2015, as well as the annualised rates of decline achieved from 2000 to 2015. Subnational areas in countries such as Botswana, Rwanda, and Ethiopia recorded some of the largest decreases in child mortality rates since 2000, positioning them well to achieve SDG targets by 2030 or earlier. Yet these places were the exception for Africa, since many areas, particularly in central and western Africa, must reduce under-5 mortality rates by at least 8·8% per year, between 2015 and 2030, to achieve the SDG 3.2 target for under-5 mortality by 2030.
In the absence of unprecedented political commitment, financial support, and medical advances, the viability of SDG 3.2 achievement in Africa is precarious at best. By producing under-5 and neonatal mortality rates at multiple levels of geospatial resolution over time, this study provides key information for decision makers to target interventions at populations in the greatest need. In an era when precision public health increasingly has the potential to transform the design, implementation, and impact of health programmes, our 5 × 5 km estimates of child mortality in Africa provide a baseline against which local, national, and global stakeholders can map the pathways for ending preventable child deaths by 2030.
Bill & Melinda Gates Foundation.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Malaria remains a major cause of death globally, especially in sub-Saharan Africa. Trends in malaria-associated mortality over the last 25 years are reported across sub-Saharan Africa.
Measuring the ...burden of malaria according to age and geographic area and over time is important for malaria-control programs and health care providers for planning, implementing, monitoring, and evaluating control and elimination efforts.
1
,
2
The Malaria Atlas Project has produced high-spatial-resolution (5-km
2
) estimates of the prevalence of malaria infection (parasite rate) and clinical incidence rates in sub-Saharan Africa from 2000 through 2015.
3
In parallel, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD), also known as the Global Burden of Disease Study, has produced national-level estimates of morbidity and mortality from malaria on an annual basis since . . .
Scope
MicroRNA are critical to the coordinated post‐transcriptional regulation of gene expression, yet few studies have addressed the influence of habitual diet on microRNA expression. High protein ...diets impact cardiometabolic health and body composition in the elderly suggesting the possibility of a complex systems response. Therefore, high‐throughput small RNA sequencing technology is applied in response to doubling the protein recommended dietary allowance (RDA) over 10 weeks in older men to examine alterations in circulating miRNAome.
Methods and Results
Older men (n = 31; 74.1 ± 0.6 y) are randomized to consume either RDA (0.8 g kg−1 day−1) or 2RDA (1.6 g kg−1 day−1) of protein for 10 weeks. Downregulation of five microRNAs (miR‐125b‐5p, ‐100‐5p, ‐99a‐5p, ‐23b‐3p, and ‐203a) is observed following 2RDA with no changes in the RDA. In silico functional analysis highlights target gene enrichment in inflammation‐related pathways. qPCR quantification of predicted inflammatory genes (TNFα, IL‐8, IL‐6, pTEN, PPP1CB, and HOXA1) in peripheral blood mononuclear cells shows increased expression following 2RDA diet (p ≤ 0.05).
Conclusion
The study findings suggest a possible selective alteration in the post‐transcriptional regulation of the immune system following a high protein diet. However, very few microRNAs are altered despite a large change in the dietary protein.
Dietary factors regulate the expression of microRNA that are important for health. High‐throughput sequencing is used to examine the circulatory miRNA response to a high protein diet. Altered abundances of miRNA implicated in the post‐transcriptional regulation of the immune system are present.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Muscle hypertrophy occurs following increased protein synthesis, which requires activation of the ribosomal complex. Additionally, increased translational capacity via elevated ribosomal RNA (rRNA) ...synthesis has also been implicated in resistance training‐induced skeletal muscle hypertrophy. The time course of ribosome biogenesis following resistance exercise (RE) and the impact exerted by differing recovery strategies remains unknown. In the present study, the activation of transcriptional regulators, the expression levels of pre‐rRNA, and mature rRNA components were measured through 48 h after a single‐bout RE. In addition, the effects of either low‐intensity cycling (active recovery, ACT) or a cold‐water immersion (CWI) recovery strategy were compared. Nine male subjects performed two bouts of high‐load RE randomized to be followed by 10 min of either ACT or CWI. Muscle biopsies were collected before RE and at 2, 24, and 48 h after RE. RE increased the phosphorylation of the p38‐MNK1‐eIF4E axis, an effect only evident with ACT recovery. Downstream, cyclin D1 protein, total eIF4E, upstream binding factor 1 (UBF1), and c‐Myc proteins were all increased only after RE with ACT. This corresponded with elevated abundance of the pre‐rRNAs (45S, ITS‐28S, ITS‐5.8S, and ETS‐18S) from 24 h after RE with ACT. In conclusion, coordinated upstream signaling and activation of transcriptional factors stimulated pre‐rRNA expression after RE. CWI, as a recovery strategy, markedly blunted these events, suggesting that suppressed ribosome biogenesis may be one factor contributing to the impaired hypertrophic response observed when CWI is used regularly after exercise.
Signalling pathway leading to rDNA transcription affected by resistance exercise and recovery strategies.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Insufficient growth during childhood is associated with poor health outcomes and an increased risk of death. Between 2000 and 2015, nearly all African countries demonstrated improvements for children ...under 5 years old for stunting, wasting, and underweight, the core components of child growth failure. Here we show that striking subnational heterogeneity in levels and trends of child growth remains. If current rates of progress are sustained, many areas of Africa will meet the World Health Organization Global Targets 2025 to improve maternal, infant and young child nutrition, but high levels of growth failure will persist across the Sahel. At these rates, much, if not all of the continent will fail to meet the Sustainable Development Goal target-to end malnutrition by 2030. Geospatial estimates of child growth failure provide a baseline for measuring progress as well as a precision public health platform to target interventions to those populations with the greatest need, in order to reduce health disparities and accelerate progress.
Full text
Available for:
KISLJ, NUK, SBMB, UL, UM, UPUK
The mammalian target of rapamycin (mTOR) complex exerts a pivotal role in protein anabolism and cell growth. Despite its importance, few studies adequately address the complexity of phosphorylation ...of the mTOR protein itself to enable conclusions to be drawn on the extent of kinase activation following this event. In particular, a large number of studies in the skeletal muscle biology field have measured Serine 2448 (Ser2448) phosphorylation as a proxy of mTOR kinase activity. However, the evidence to be described is that Ser2448 is not a measure of mTOR kinase activity nor is a target of AKT activity and instead has inhibitory effects on the kinase that is targeted by the downstream effector p70S6K in a negative feedback loop mechanism, which is evident when revisiting muscle research studies. It is proposed that this residue modification acts as a fine-tuning mechanism that has been gained during vertebrate evolution. In conclusion, it is recommended that Ser2448 is an inadequate measure and that preferential analysis of mTORC1 activation should focus on the downstream and effector proteins, including p70S6K and 4E-BP1, along mTOR protein partners that bind to mTOR protein to form the active complexes 1 and 2.
Full text
Available for:
EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
New Findings
What is the central question of this study?
Although acute responses of the principal gonadosteroid and corticosteroid hormones to resistance exercise are well documented, there is no ...information regarding how the key lower‐concentration intermediary hormones respond and potentially influence these hormonal pathways.
What is the main finding and its importance?
This study provides evidence for cascading conversions of some gonadosteroids, and the data suggest that the testosterone concentration increases independently of these hormones. These findings challenge future studies to determine the exact physiological roles of the lower‐concentration gonadosteroids and corticosteroids during and immediately after resistance exercise.
Resistance training is a potent stimulus for muscle growth, and steroid hormones are known to play a role in this adaptation. However, very little is known about the acute exercise‐induced gonadosteroid and corticosteroid hormone responses, including those of key lower‐concentration intermediate hormones. The present study determined the acute responses of these steroid hormone families using quantitative ultra‐high performance liquid chromatography tandem mass spectrometry after resistance exercise in strength‐trained men. Venous and fingertip blood samples were obtained pre‐, mid‐, 5 min post‐ and 15 min post‐resistance exercise, both before and after 10 weeks of supervised resistance training. The experimental resistance exercise sessions consisted of three sets of 10 repetitions of bilateral leg‐press exercise and three sets of 10 repetitions of unilateral knee‐extension exercise, with 2 and 1 min recovery between sets, respectively. Statistically significant (P < 0.05) increases in the concentration of hormones in the gonadosteroid including dehydroepiandrosterone (DHEA), androstenedione, testosterone and estrone and the corticosteroid (including cortisol, corticosterone and cortisone) families were demonstrated after both experimental resistance exercise sessions, irrespective of training status. Correlation analyses revealed relationships between the following hormones: (i) DHEA and androstenedione; (ii) DHEA and cortisol; (iii) androstenedione and estrone; and (iv) 11‐deoxycortisol and cortisol. Testosterone appears to increase acutely and independently of other intermediary hormones after resistance exercise. In conclusion, lower‐concentration intermediary gonadosteroids (e.g. estrone) and corticosteroids (e.g. corticosterone) respond robustly to resistance exercise in strength‐trained men, although it seems that testosterone concentrations are regulated by factors other than the availability of precursor hormones and changes in plasma volume.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Humanin is a small regulatory peptide encoded within the 16S ribosomal RNA gene (
) of the mitochondrial genome that has cellular cyto- and metabolo-protective properties similar to that of aerobic ...exercise training. Here we investigated whether acute high-intensity interval exercise or short-term high-intensity interval training (HIIT) impacted skeletal muscle and plasma humanin levels. Vastus lateralis muscle biopsies and plasma samples were collected from young healthy untrained men (
= 10, 24.5 ± 3.7 yr) before, immediately following, and 4 h following the completion of 10 × 60 s cycle ergometer bouts at V̇o
power output (untrained). Resting and postexercise sampling was also performed after six HIIT sessions (trained) completed over 2 wk. Humanin protein abundance in muscle and plasma were increased following an acute high-intensity exercise bout. HIIT trended (
= 0.063) to lower absolute humanin plasma levels, without effecting the response in muscle or plasma to acute exercise. A similar response in the plasma was observed for the small humanin-like peptide 6 (SHLP6), but not SHLP2, indicating selective regulation of peptides encoded by MT-RNR2 gene. There was a weak positive correlation between muscle and plasma humanin levels, and contraction of isolated mouse EDL muscle increased humanin levels ~4-fold. The increase in muscle humanin levels with acute exercise was not associated with
mRNA or
mRNA levels (which decreased following acute exercise). Overall, these results suggest that humanin is an exercise-sensitive mitochondrial peptide and acute exercise-induced humanin responses in muscle are nontranscriptionally regulated and may partially contribute to the observed increase in plasma concentrations.
Small regulatory peptides encoded within the mitochondrial genome (mitochondrial derived peptides) have been shown to have cellular cyto- and metabolo-protective roles that parallel those of exercise. Here we provide evidence that humanin and SHLP6 are exercise-sensitive mitochondrial derived peptides. Studies to determine whether mitochondrial derived peptides play a role in regulating exercise-induced adaptations are warranted.
PDF
