bims-kimdis 2023-05-28 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2023‒05‒28
thirteen papers selected by
Matías Javier Monsalves Álvarez

Investigating the Link between Ketogenic Diet, NAFLD, Mitochondria, and Oxidative Stress: A Narrative Review.
Metabolic markers of short and long-term exogenous DL-beta-hydroxybutyrate supplementation in episodic migraine patients: an exploratory analysis of a randomized-controlled-trial.
Chronotype as a predictor of weight loss and body composition improvements in women with overweight or obesity undergoing a very low-calorie ketogenic diet (VLCKD).
Effects of ketogenic diet on health outcomes: an umbrella review of meta-analyses of randomized clinical trials.
OXCT1 regulates NF-κB signaling pathway through β-hydroxybutyrate-mediated ketone body homeostasis in lung cancer.
Long-Term Effects of a Ketogenic Diet for Cancer.
Exercise metabolism and adaptation in skeletal muscle.
Modified Atkins Diet vs. Ketogenic Diet in the Management of Children with Epileptic Spasms Refractory to First Line Treatment: An Open Labelled, Randomized Controlled Trial.
Mitochondrial transplantation as a possible therapeutic option for sarcopenia.
Association between skeletal muscle mitochondrial dysfunction and insulin resistance in patients with rheumatoid arthritis: a case-control study.
Effects of Whey Protein Isolate on Body Composition, Muscle Mass, and Strength of Chronic Heart Failure Patients: A Randomized Clinical Trial.
Mechanisms of slowed V̇O2 on-kinetics in second step of two-step-incremental exercise in skeletal muscle.
Physical activity impacts resting skeletal muscle myosin conformation and lowers its ATP consumption.

Antioxidants (Basel). 2023 May 08. pii: 1065. [Epub ahead of print]12(5):

Investigating the Link between Ketogenic Diet, NAFLD, Mitochondria, and Oxidative Stress: A Narrative Review.

Antonio Paoli, Giuseppe Cerullo.

  Together with the global rise in obesity and metabolic syndrome, the prevalence of individuals who suffer from nonalcoholic fatty liver disease (NAFLD) has risen dramatically. NAFLD is currently the most common chronic liver disease and includes a continuum of liver disorders from initial fat accumulation to nonalcoholic steatohepatitis (NASH), considered the more severe forms, which can evolve in, cirrhosis, and hepatocellular carcinoma. Common features of NAFLD includes altered lipid metabolism mainly linked to mitochondrial dysfunction, which, as a vicious cycle, aggravates oxidative stress and promotes inflammation and, as a consequence, the progressive death of hepatocytes and the severe form of NAFLD. A ketogenic diet (KD), i.e., a diet very low in carbohydrates (<30 g/die) that induces "physiological ketosis", has been demonstrated to alleviate oxidative stress and restore mitochondrial function. Based on this, the aim of the present review is to analyze the body of evidence regarding the potential therapeutic role of KD in NAFLD, focusing on the interplay between mitochondria and the liver, the effects of ketosis on oxidative stress pathways, and the impact of KD on liver and mitochondrial function.

Keywords:  ketogenic diet; ketone bodies; liver; mitochondria; nonalcoholic fatty liver disease (NAFLD); oxidative stress

DOI:  https://doi.org/10.3390/antiox12051065
Front Pharmacol. 2023 ;14 1172483

Metabolic markers of short and long-term exogenous DL-beta-hydroxybutyrate supplementation in episodic migraine patients: an exploratory analysis of a randomized-controlled-trial.

Niveditha Putananickal, Elena C Gross, Anna-Lena Orsini, Simone Schmidt, Patricia Hafner, Vanya Gocheva, Sara Nagy, Bettina C Henzi, Daniela Rubino, Sabine Schädelin, Peter Sandor, Dirk Fischer.

  Background: Emerging findings propose that the pathophysiology of migraine may be associated with dysfunctional metabolic mechanisms. Recent findings suggest that migraine attacks are a response to the cerebral energy deficit, and ingestion of ketone bodies stabilizes the generation of a migraine attack. Based on these findings, ketone body supplementation is postulated as a prophylactic treatment approach to restore cerebral metabolism deficiency. Metabolic markers are unexplored after exogenous ketone body supplementation in episodic migraineurs. Therefore, the present single-arm uncontrolled explorative analysis evaluated blood ketone body and glucose concentration after short and long-term 6 g exogenous DL-Mg-Ca-beta-hydroxybutyrate (DL-βHB) supplementation. Methods: The presented data are part of the MigraKet randomized-control cross-over clinical trial of 41 episodic migraineurs (Number NCT03132233). Patients were given a single dose of 6 g DL-βHB. Ketone body and glucose blood concentration were assessed before intake, 20, and 40 min after DL-βHB intake. Ketone body, glucose concentration and glycated hemoglobin values were evaluated after 12 weeks of 18 g DL-βHB ingestion (total dose), taken three times daily (6g/dose; 3x/day). Linear models explored the association between the ketone body and glucose levels. Results: Ketone body concentration increased within-group to a mean of 0.46 (0.30) mmol/L after 40 min post- DL-βHB supplementation [estimate = 0.24 mmol/L, CI = (0.20.0.27), p < 0.01]. This within-group increase of ketone body concentration did not change after repeated daily intake of DL-βHB supplementation over 12 weeks [estimate = 0.00 mmol/L, CI = (-0.03.0.04), p = 0.794]. DL-βHB intake significantly reduced blood glucose concentration within-group from a mean baseline of 4.91 (0.42) mmol/L to 4.75 (0.47) mmol/L 40 min post-DL-βHB supplementation [estimate = -0.16 mmol/L, CI = (-0.15, 0.03), p < 0.01]. Repeated DL-βHB supplementation for 12 weeks showed no change within-group in acute ketone bodies concentration [estimate = 0.00 mmol/L, CI = (-0.03.0.04), p = 0.794] and in the HbA1c value [estimate = 0.02, CI = (-0.07.0.11), p = 0.69]. Conclusion: A single dose of 6 g DL-βHB significantly elevated blood ketone bodies and decreased blood glucose concentration within-group in episodic migraineurs. Long-term DL-βHB supplementation for 12 weeks showed no effect within-group on acute ketone body concentration and had not impact on HbA1c. The elevation of the ketone body concentration was moderate, indicating that nutritional ketosis was not reached. Therefore, a dose higher than 6 g of DL-βHB is required to reach the nutritional level of ketosis. ClinicalTrials.gov Identifier: NCT03132233.

Keywords:  DL-Mg-Ca-beta-hydroxybutyrate; exogenous ketone bodies; ketone salt; long-term ketone supplementation; migraine

DOI:  https://doi.org/10.3389/fphar.2023.1172483
Clin Nutr. 2023 May 19. pii: S0261-5614(23)00156-5. [Epub ahead of print]

Chronotype as a predictor of weight loss and body composition improvements in women with overweight or obesity undergoing a very low-calorie ketogenic diet (VLCKD).

Ludovica Verde, Luigi Barrea, Annamaria Docimo, Silvia Savastano, Annamaria Colao, Giovanna Muscogiuri.

  BACKGROUND & AIM: Recent studies reported that chronotype play a role in the development of metabolic comorbidities and in determining dietary habits in obesity. However, little is known if chronotype could predict the efficacy of nutritional approaches for obesity. The aim of this study was to investigate whether chronotype categories can have a role in determining the efficacy of very low-calorie ketogenic diet (VLCKD) in terms of weight loss and changes of body composition in women with overweight or obesity.METHODS: In this retrospective study we analyzed data from 248 women (BMI 36.03 ± 5.20 kg/m2, aged 38.76 ± 14.05 years) clinically referred for weight loss and who completed a VLCKD program. In all women, we assessed anthropometric parameters (weight, height, and waist circumference), body composition and phase angle (through bioimpedance analysis, Akern BIA 101) at the baseline and after 31 days of active phase of VLCKD. Chronotype score was assessed using Morningness-Eveningness questionnaire (MEQ) at baseline.
RESULTS: After 31 days of active phase of VLCKD all enrolled women experienced significant weight loss (p < 0.001) and reduction of BMI (p < 0.001), waist circumference (p < 0.001), fat mass (kg and %) (p < 0.001), and free fat mass (kg) (p < 0.001). Women with evening chronotype experienced significantly less weight loss (p < 0.001) and reduced fat mass (kg and %) (p < 0.001), increased fat free mass (kg and %) (p < 0.001) and phase angle (p < 0.001) than women with morning chronotype. In addition, chronotype score correlated negatively with percentage changes in weight (p < 0.001), BMI (p < 0.001), waist circumference (p < 0.001) and fat mass (p < 0.001) and positively with fat free mass (p < 0.001) and phase angle (p < 0.001) from baseline to the 31st day of active phase of VLCKD. Using a linear regression model, chronotype score (p < 0.001) was the main predictors of weight loss achieved with VLCKD.
CONCLUSION: Evening chronotype is associated with a lower efficacy in terms of weight loss and improvements of body composition after VLCKD in obesity.

Keywords:  Chronotype; Diet; Nutrition; Obesity; VLCKD; Very low-calorie ketogenic diet; Weight loss

DOI:  https://doi.org/10.1016/j.clnu.2023.05.014
BMC Med. 2023 May 25. 21(1): 196

Effects of ketogenic diet on health outcomes: an umbrella review of meta-analyses of randomized clinical trials.

Chanthawat Patikorn, Pantakarn Saidoung, Tuan Pham, Pochamana Phisalprapa, Yeong Yeh Lee, Krista A Varady, Sajesh K Veettil, Nathorn Chaiyakunapruk.

  BACKGROUND: Systematic reviews and meta-analyses of randomized clinical trials (RCTs) have reported the benefits of ketogenic diets (KD) in various participants such as patients with epilepsy and adults with overweight or obesity. Nevertheless, there has been little synthesis of the strength and quality of this evidence in aggregate.METHODS: To grade the evidence from published meta-analyses of RCTs that assessed the association of KD, ketogenic low-carbohydrate high-fat diet (K-LCHF), and very low-calorie KD (VLCKD) with health outcomes, PubMed, EMBASE, Epistemonikos, and Cochrane database of systematic reviews were searched up to February 15, 2023. Meta-analyses of RCTs of KD were included. Meta-analyses were re-performed using a random-effects model. The quality of evidence per association provided in meta-analyses was rated by the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) criteria as high, moderate, low, and very low.
RESULTS: We included 17 meta-analyses comprising 68 RCTs (median [interquartile range, IQR] sample size of 42 [20-104] participants and follow-up period of 13 [8-36] weeks) and 115 unique associations. There were 51 statistically significant associations (44%) of which four associations were supported by high-quality evidence (reduced triglyceride (n = 2), seizure frequency (n = 1) and increased low-density lipoprotein cholesterol (LDL-C) (n = 1)) and four associations supported by moderate-quality evidence (decrease in body weight, respiratory exchange ratio (RER), hemoglobin A1c, and increased total cholesterol). The remaining associations were supported by very low (26 associations) to low (17 associations) quality evidence. In overweight or obese adults, VLCKD was significantly associated with improvement in anthropometric and cardiometabolic outcomes without worsening muscle mass, LDL-C, and total cholesterol. K-LCHF was associated with reduced body weight and body fat percentage, but also reduced muscle mass in healthy participants.
CONCLUSIONS: This umbrella review found beneficial associations of KD supported by moderate to high-quality evidence on seizure and several cardiometabolic parameters. However, KD was associated with a clinically meaningful increase in LDL-C. Clinical trials with long-term follow-up are warranted to investigate whether the short-term effects of KD will translate to beneficial effects on clinical outcomes such as cardiovascular events and mortality.

Keywords:  Ketegenic diet; Meta-analysis; Seizure; Systematic review; Umbrella review; Weight loss

DOI:  https://doi.org/10.1186/s12916-023-02874-y
Genes Dis. 2023 Mar;10(2): 352-355

OXCT1 regulates NF-κB signaling pathway through β-hydroxybutyrate-mediated ketone body homeostasis in lung cancer.

Zhuo Lu, Tianyu Han, Tao Wang, Mingxi Gan, Caifeng Xie, Bentong Yu, Jian-Bin Wang.

DOI: https://doi.org/10.1016/j.gendis.2022.04.020
Nutrients. 2023 May 16. pii: 2334. [Epub ahead of print]15(10):

Long-Term Effects of a Ketogenic Diet for Cancer.

Ryuichiro Egashira, Michiko Matsunaga, Akimitsu Miyake, Sayaka Hotta, Naoko Nagai, Chise Yamaguchi, Mariko Takeuchi, Misaki Moriguchi, Satoko Tonari, Mai Nakano, Hitomi Saito, Keisuke Hagihara.

  A ketogenic diet has been proposed as a potential supportive therapy for cancer patients, although its long-term influence on survival rates remain controversial. In our previous report, we presented promising results for 37 of 55 patients with advanced cancer enrolled between 2013 and 2018 who remained on a ketogenic diet for at least 3 months. We followed all 55 patients until March 2023 and analyzed the data up to March 2022. For the 37 patients with previously reported promising results, the median follow-up period was 25 (range of 3-104) months and 28 patients died. The median overall survival (OS) in this subset of 37 patients was 25.1 months and the 5-year survival rate was 23.9%. We also evaluated the association between the duration of the ketogenic diet and outcome in all 55 patients, except for 2 patients with insufficient data. The patients were divided into two groups: those who followed the diet for ≥12 months (n = 21) and those who followed it for <12 months (n = 32). The median duration of the ketogenic diet was 37 (range of 12-99) months for the ≥12 months group and 3 (range of 0-11) months for the <12 months group. During the follow-up period, 41 patients died (10/21 in the ≥12 months group and 31/32 in the <12 months group). The median OS was 19.9 months (55.1 months in the ≥12 months group and 12 months in the <12 months group). Following the inverse probability of treatment weighting to align the background factors of the two groups and make them comparable, the adjusted log-rank test showed a significantly better OS rate in the group that continued the ketogenic diet for a longer period (p < 0.001, adjusted log-rank test). These results indicate that a longer continuation of the ketogenic diet improved the prognosis of advanced cancer patients.

Keywords:  cancer; ketogenic diet; long-term effect; propensity score weighting

DOI:  https://doi.org/10.3390/nu15102334
Nat Rev Mol Cell Biol. 2023 May 24.

Exercise metabolism and adaptation in skeletal muscle.

Jonathon A B Smith, Kevin A Murach, Kenneth A Dyar, Juleen R Zierath.

Viewing metabolism through the lens of exercise biology has proven an accessible and practical strategy to gain new insights into local and systemic metabolic regulation. Recent methodological developments have advanced understanding of the central role of skeletal muscle in many exercise-associated health benefits and have uncovered the molecular underpinnings driving adaptive responses to training regimens. In this Review, we provide a contemporary view of the metabolic flexibility and functional plasticity of skeletal muscle in response to exercise. First, we provide background on the macrostructure and ultrastructure of skeletal muscle fibres, highlighting the current understanding of sarcomeric networks and mitochondrial subpopulations. Next, we discuss acute exercise skeletal muscle metabolism and the signalling, transcriptional and epigenetic regulation of adaptations to exercise training. We address knowledge gaps throughout and propose future directions for the field. This Review contextualizes recent research of skeletal muscle exercise metabolism, framing further advances and translation into practice.

DOI: https://doi.org/10.1038/s41580-023-00606-x
Indian J Pediatr. 2023 May 26.

Modified Atkins Diet vs. Ketogenic Diet in the Management of Children with Epileptic Spasms Refractory to First Line Treatment: An Open Labelled, Randomized Controlled Trial.

Shobhna Sharma, Surekha Dabla, Jaya Shankar Kaushik.

  OBJECTIVE: To compare the efficacy and tolerability of modified Atkins diet (mAD) and ketogenic diet (KD) among children aged 9 mo to 3 y with epileptic spasms refractory to the first line treatment.METHODS: An open labelled, randomized controlled trial with parallel group assignment was conducted among children aged 9 mo to 3 y with epileptic spasms refractory to the first line treatment. They were randomized to either receive the mAD along with conventional anti-seizure medications (n = 20) or KD with conventional anti-seizure medications (n = 20). Primary outcome measure was proportion of children who achieved "spasm freedom" at 4 wk and 12 wk. Secondary outcome measures were proportion of children who achieved >50% and >90% reduction in spasms at 4 wk and 12 wk, nature and proportion of the adverse effects as per parental reports.
RESULTS: Proportion of children achieving spasm freedom [mAD {4 (20%)} vs. KD {3 (15%)}: OR (95% CI) 1.42 (0.27-7.34); P = 0.67], >50% spasm reduction [mAD {3 (15%)} vs. KD {5 (25%)}: OR (95% CI) 0.53 (0.11-2.59); P = 0.63] and >90% spasm reduction [mAD {4 (20%)} vs. KD {2 (10%)}: OR (95% CI) 2.25 (0.36-13.97); P = 0.41] was comparable between the two groups at 12 wk. The diet was well tolerated in both the groups with vomiting and constipation being the most common reported adverse effect.
CONCLUSIONS: mAD is an effective alternative to KD in the management of children with epileptic spasms refractory to first line treatment. However, further studies with adequately powered sample size and longer follow-up are required.
TRIAL REGISTRATION: CTRI/2020/03/023791.

Keywords:  ACTH; Hypsarrhythmia; Prednisolone; West syndrome

DOI:  https://doi.org/10.1007/s12098-023-04527-7
J Mol Med (Berl). 2023 May 20.

Mitochondrial transplantation as a possible therapeutic option for sarcopenia.

Ibrahim Turkel, Berkay Ozerklig, Merve Yılmaz, Oner Ulger, Gokhan Burcin Kubat, Meltem Tuncer.

  With advancing age, the skeletal muscle phenotype is characterized by a progressive loss of mass, strength, and quality. This phenomenon, known as sarcopenia, has a negative impact on quality of life and increases the risk of morbidity and mortality in older adults. Accumulating evidence suggests that damaged and dysfunctional mitochondria play a critical role in the pathogenesis of sarcopenia. Lifestyle modifications, such as physical activity, exercise, and nutrition, as well as medical interventions with therapeutic agents, are effective in the management of sarcopenia and offer solutions to maintain and improve skeletal muscle health. Although a great deal of effort has been devoted to the identification of the best treatment option, these strategies are not sufficient to overcome sarcopenia. Recently, it has been reported that mitochondrial transplantation may be a possible therapeutic approach for the treatment of mitochondria-related pathological conditions such as ischemia, liver toxicity, kidney injury, cancer, and non-alcoholic fatty liver disease. Given the role of mitochondria in the function and metabolism of skeletal muscle, mitochondrial transplantation may be a possible option for the treatment of sarcopenia. In this review, we summarize the definition and characteristics of sarcopenia and molecular mechanisms associated with mitochondria that are known to contribute to sarcopenia. We also discuss mitochondrial transplantation as a possible option. Despite the progress made in the field of mitochondrial transplantation, further studies are needed to elucidate the role of mitochondrial transplantation in sarcopenia. KEY MESSAGES: Sarcopenia is the progressive loss of skeletal muscle mass, strength, and quality. Although the specific mechanisms that lead to sarcopenia are not fully understood, mitochondria have been identified as a key factor in the development of sarcopenia. Damaged and dysfunctional mitochondria initiate various cellular mediators and signaling pathways, which largely contribute to the age-related loss of skeletal muscle mass and strength. Mitochondrial transplantation has been reported to be a possible option for the treatment/prevention of several diseases. Mitochondrial transplantation may be a possible therapeutic option for improving skeletal muscle health and treating sarcopenia. Mitochondrial transplantation as a possible treatment option for sarcopenia.

Keywords:  Mitochondrial dysfunction; Mitochondrial transplantation; Sarcopenia; Skeletal muscle

DOI:  https://doi.org/10.1007/s00109-023-02326-3
Arthritis Res Ther. 2023 05 20. 25(1): 85

Association between skeletal muscle mitochondrial dysfunction and insulin resistance in patients with rheumatoid arthritis: a case-control study.

Douglas R Moellering, Kelley Smith-Johnston, Christian Kelley, Melissa J Sammy, Jason Benedict, Guy Brock, Jillian Johnson, Kedryn K Baskin, Wael N Jarjour, Martha A Belury, Peter J Reiser, Prabhakara R Nagareddy, Beatriz Y Hanaoka.

  BACKGROUND: Insulin resistance affects a substantial proportion of patients with rheumatoid arthritis (RA). Skeletal muscle mitochondrial dysfunction results in the accumulation of lipid intermediates that interfere with insulin signaling. We therefore sought to determine if lower oxidative phosphorylation and muscle mitochondrial content are associated with insulin resistance in patients with RA.METHODS: This was a cross-sectional prospective study of RA patients. Matsuda index from the glucose tolerance test was used to estimate insulin sensitivity. Mitochondrial content was measured by citrate synthase (CS) activity in snap-frozen muscle samples. Mitochondrial function was measured by using high-resolution respirometry of permeabilized muscle fibers and electron transport chain complex IV enzyme kinetics in isolated mitochondrial subpopulations.
RESULTS: RA participants demonstrated lower insulin sensitivity as measured by the Matsuda index compared to controls [median 3.95 IQR (2.33, 5.64) vs. 7.17 (5.83, 7.75), p = 0.02]. There was lower muscle mitochondrial content among RA vs. controls [median 60 mU/mg IQR (45, 80) vs. 79 mU/mg (65, 97), p = 0.03]. Notably, OxPhos normalized to mitochondrial content was higher among RA vs. controls [mean difference (95% CI) = 0.14 (0.02, 0.26), p = 0.03], indicating a possible compensatory mechanism for lower mitochondrial content or lipid overload. Among RA participants, the activity of muscle CS activity was not correlated with the Matsuda index (ρ = - 0.05, p = 0.84), but it was positively correlated with self-reported (IPAQ) total MET-minutes/week (ρ = 0.44, p = 0.03) and Actigraph-measured time on physical activity (MET rate) (ρ = 0.47, p = 0.03).
CONCLUSIONS: Mitochondrial content and function were not associated with insulin sensitivity among participants with RA. However, our study demonstrates a significant association between muscle mitochondrial content and physical activity level, highlighting the potential for future exercise interventions that enhance mitochondrial efficiency in RA patients.

Keywords:  Mitochondria; Rheumatoid arthritis; Skeletal muscle

DOI:  https://doi.org/10.1186/s13075-023-03065-z
Nutrients. 2023 May 16. pii: 2320. [Epub ahead of print]15(10):

Effects of Whey Protein Isolate on Body Composition, Muscle Mass, and Strength of Chronic Heart Failure Patients: A Randomized Clinical Trial.

Elisa M Dos Santos, Annie S B Moreira, Grazielle V B Huguenin, Eduardo Tibiriça, Andrea De Lorenzo.

  Heart failure (HF) is associated with a reduction of skeletal muscle mass. Whey protein isolate (WPI) has been beneficial in increasing muscle mass and strength, in addition to improving body composition. The goal of this research was to evaluate the effect of WPI on the body composition, muscle mass, and strength of chronic HF patients. For this purpose, twenty-five patients of both genders with predominantly NYHA I functional class and a median age of 65.5 (60.5-71.0) years were used to conduct a randomized, single-blind, placebo-controlled clinical trial and received 30 g per day of WPI for 12 weeks. Anthropometric measurements, body composition analysis, and biochemical exams were performed at the beginning and end of the study. An increase in skeletal muscle mass was observed in the intervention group after 12 weeks. A reduction in waist circumference, body fat percentage, and an increase in skeletal muscle index was observed when compared to the placebo group. No significant effect on muscle strength was observed after 12 weeks of intervention. These data demonstrate that WPI consumption contributed to the increase of skeletal muscle mass, strength, and reduction of body fat in HF patients.

Keywords:  diet; heart failure; muscle strength; randomized clinical trial; whey proteins

DOI:  https://doi.org/10.3390/nu15102320
Respir Physiol Neurobiol. 2023 May 23. pii: S1569-9048(23)00072-1. [Epub ahead of print] 104084

Mechanisms of slowed V̇O2 on-kinetics in second step of two-step-incremental exercise in skeletal muscle.

Bernard Korzeniewski.

  Simulations using a computer model of the skeletal muscle bioenergetic system demonstrate that the slowed V̇O2 on-kinetics of the second step in two-step incremental exercise (exercise initiated from elevated baseline metabolic rate) can be accounted for by a decrease in the stimulation of oxidative phosphorylation (OXPHOS) and/or increase in the stimulation of glycolysis through each-step activation (ESA) in working skeletal muscle. This effect can be caused by either a recruitment of more glycolytic type IIa, IIx and IIb fibers or metabolic regulation in already recruited fibers, or both. The elevated-glycolysis-stimulation mechanism predicts that the end-second-step pH in two-step-incremental exercise is lower than the end-exercise pH in constant-power exercise with the same work intensity (power output). The lowered-OXPHOS-stimulation mechanism predicts higher end-exercise ADP and Pi, and lower PCr in the second step of two-step-incremental than in constant-power exercise. These predictions/mechanisms can be verified or falsified in the experimental way. DATA AVAILABILITY STATEMENT: There are no additional data available.

Keywords:  constant-power exercise; elevated baseline metabolic rate; muscle fiber recruitment; oxygen uptake kinetics; skeletal muscle; step-incremental exercise

DOI:  https://doi.org/10.1016/j.resp.2023.104084
J Gen Physiol. 2023 Jul 03. pii: e202213268. [Epub ahead of print]155(7):

Physical activity impacts resting skeletal muscle myosin conformation and lowers its ATP consumption.

Christopher T A Lewis, Lee Tabrizian, Joachim Nielsen, Jenni Laitila, Thomas N Beck, Mathilde S Olsen, Marija M Ognjanovic, Per Aagaard, Rune Hokken, Simon Laugesen, Arthur Ingersen, Jesper L Andersen, Casper Soendenbroe, Jørn W Helge, Flemming Dela, Steen Larsen, Ronni E Sahl, Tue Rømer, Mikkel T Hansen, Jacob Frandsen, Charlotte Suetta, Julien Ochala.

It has recently been established that myosin, the molecular motor protein, is able to exist in two conformations in relaxed skeletal muscle. These conformations are known as the super-relaxed (SRX) and disordered-relaxed (DRX) states and are finely balanced to optimize ATP consumption and skeletal muscle metabolism. Indeed, SRX myosins are thought to have a 5- to 10-fold reduction in ATP turnover compared with DRX myosins. Here, we investigated whether chronic physical activity in humans would be associated with changes in the proportions of SRX and DRX skeletal myosins. For that, we isolated muscle fibers from young men of various physical activity levels (sedentary, moderately physically active, endurance-trained, and strength-trained athletes) and ran a loaded Mant-ATP chase protocol. We observed that in moderately physically active individuals, the amount of myosin molecules in the SRX state in type II muscle fibers was significantly greater than in age-matched sedentary individuals. In parallel, we did not find any difference in the proportions of SRX and DRX myosins in myofibers between highly endurance- and strength-trained athletes. We did however observe changes in their ATP turnover time. Altogether, these results indicate that physical activity level and training type can influence the resting skeletal muscle myosin dynamics. Our findings also emphasize that environmental stimuli such as exercise have the potential to rewire the molecular metabolism of human skeletal muscle through myosin.

DOI: https://doi.org/10.1085/jgp.202213268