bims-kimdis 2025-03-02 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2025–03–02
twenty-two papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

A Randomized Open-Label, Observational Study of the Novel Ketone Ester, Bis Octanoyl (R)-1,3-Butanediol, and Its Acute Effect on ß-Hydroxybutyrate and Glucose Concentrations in Healthy Older Adults.
Illnesses associated with ketosis including diabetic ketoacidosis during very low carbohydrate and ketogenic diets.
Endogenous Ketone Bodies Are Associated with Metabolic Vulnerability and Disability in Multiple Sclerosis.
The Influence of Physical Exercise, Ketogenic Diet, and Time-Restricted Eating on De Novo Lipogenesis: A Narrative Review.
Advanced Footwear Technology, but not Acute Ingestion of a Ketone Monoester, Improves Running Economy in Middle- and Long-Distance Runners.
A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity.
A pilot study of a ketogenic diet in bipolar disorder: clinical, metabolic and magnetic resonance spectroscopy findings.
Carnitine supplementation improves insulin sensitivity and skeletal muscle acetylcarnitine formation in patients with type 2 diabetes.
Unsaturated Fatty Acids Enhance Mitochondrial Function and PGC1-α Expression in Brown Adipose Tissue of Obese Mice on a Low-Carbohydrate Diet.
Oral contraceptive pill phase does not influence muscle protein synthesis or myofibrillar proteolysis at rest or in response to resistance exercise.
The effects of high protein intakes during energy restriction on body composition, energy metabolism and physical performance in recreational athletes.
Mitochondrial substrate oxidation regulates distinct cell differentiation outcomes.
Transcriptomic adaptation of skeletal muscle in response to MICT and HIIT exercise modalities.
Cardiac energy metabolism is decreased in male volunteers with prediabetes and does not normalize during the day.
How quickly are you ageing? What molecular 'clocks' can tell you about your health.
Mitochondrial respiration capacity impacts gill tissue regeneration in Atlantic salmon.
Effects of exercise modalities on physical function and quality of life in patients with heart failure: A systematic review and network meta-analysis.
The Role of Dairy in Human Nutrition: Myths and Realities.
ER-mitochondria contact sites: a refuge for mitochondrial mRNAs under ER stress.
MCC950 Reduces the Anxiodepressive-like Behaviors and Memory Deficits Related to Paclitaxel-Induced Peripheral Neuropathy in Mice.
Physical Exercise and Sleep Quality Among Chinese College Students: The Mediating Role of Self-Control and the Moderating Role of Mindfulness.
How the Topology of the Mitochondrial Inner Membrane Modulates ATP Production.

J Nutr Gerontol Geriatr. 2025 Feb 22. 1-20

A Randomized Open-Label, Observational Study of the Novel Ketone Ester, Bis Octanoyl (R)-1,3-Butanediol, and Its Acute Effect on ß-Hydroxybutyrate and Glucose Concentrations in Healthy Older Adults.

Elizabeth B Stephens, Chatura Senadheera, Stephanie Roa-Diaz, Sawyer Peralta, Laura Alexander, Wendie Silverman-Martin, Michi Yukawa, Jennifer Morris, James B Johnson, John C Newman, Brianna J Stubbs.

  Bis-octanoyl-(R)-1,3-butanediol (BO-BD) is a novel ketone ester (KE) ingredient which increases blood beta-hydroxybutyrate (BHB) concentration rapidly after ingestion. KE is hypothesized to improve function in older adults. Whilst many studies have investigated KE in young adults, they have not been studied in healthy older adults (HOA), for whom age-related differences in metabolism may alter the effects. This randomized, observational, open-label study in HOA (n = 30, 50% male, age = 76.5y) aimed to elucidate tolerance, blood BHB and glucose concentrations for 4h following consumption of either 12.5 or 25 g of BO-BD formulated in ready-to-drink beverage (n = 30), and re-constituted powder (n = 21) with a meal. All study interventions were well tolerated, and increased blood BHB, inducing nutritional ketosis (≥0.5 mM) until the end of the study. Peak BHB concentration (Cmax) and incremental area under the curve (iAUC) were significantly greater with 25 vs 12.5 g of BO-BD in both formulations. There were no significant differences in Cmax or iAUC between formulations. Blood glucose increased in all conditions following the meal, with no consistent significant differences between conditions. These results demonstrate that both powder and beverage formulations of the KE, BO-BD, induce ketosis in HOA adults, facilitating future research on functional effects of KE in aging.

Keywords:  Ketones; beta-hydroxybutyrate; exogenous ketone; ketone di-ester; ketone ester

DOI:  https://doi.org/10.1080/21551197.2025.2466163
Diabetes Obes Metab. 2025 Feb 25.

Illnesses associated with ketosis including diabetic ketoacidosis during very low carbohydrate and ketogenic diets.

Caroline G P Roberts, Shaminie J Athinarayanan, Robert E Ratner, Guillermo E Umpierrez.

   AIMS: Ketogenic diets are used by individuals with obesity and type 2 diabetes for improved glycaemic control, reduced appetite and weight loss. However, the risks associated with higher ketone levels, including diabetic ketoacidosis (DKA), in individuals with and without diabetes are not well-documented.
MATERIALS AND METHODS: We analysed real world data from a single-centre telemedicine clinic specializing in a very low carbohydrate ketogenic diet (VLCKD) as a lifestyle intervention. Illnesses associated with ketosis (IAK) were defined as beta-hydroxybutyrate (BHB) levels ≥3 mmol/L when patients sought in-person care. We estimated the IAK and DKA incidence rate in individuals with and without type 2 diabetes.
RESULTS: In 72 751 patient-years of follow-up, 86 people had IAK (incidence rate 1.18 per 1000 person-years). In 22 347 patient-years of follow-up of people without diabetes, the incidence rate of IAK was 0.04 per 1000 person-years with no DKA cases. In 50 404 patient-years of follow-up in people with type 2 diabetes (PWD), the incidence rates of IAK and of DKA were 1.69 and 1.01 per 1000 person-years, respectively. In 12 763 person-years of follow-up of PWD using SGLT2-inhibitors, the DKA incidence was 2.90 per 1000 patient-years.
CONCLUSIONS: Very low carbohydrate ketogenic diets are generally safe with low rates of IAK, including DKA, in people with and without type 2 diabetes. The higher incidence of DKA in PWD on VLCKD who are also on SGLT2-inhibitors may be manageable through at-home monitoring of BHB levels.

Keywords:  SGLT2 inhibitor; diabetes complications; dietary intervention; real‐world evidence; type 2 diabetes

DOI:  https://doi.org/10.1111/dom.16252
Nutrients. 2025 Feb 11. pii: 640. [Epub ahead of print]17(4):

Endogenous Ketone Bodies Are Associated with Metabolic Vulnerability and Disability in Multiple Sclerosis.

Taylor R Wicks, Irina Shalaurova, Anna Wolska, Richard W Browne, Bianca Weinstock-Guttman, Robert Zivadinov, Alan T Remaley, James D Otvos, Murali Ramanathan.

  Purpose: Ketone bodies could be useful biomarkers in multiple sclerosis (MS) because the pathophysiological processes underlying MS disease progression induce metabolic stress. The purpose was to assess the relationships of ketone bodies with biomarkers of metabolic, inflammatory, and oxidative stress in MS. Methods: Blood samples and neurological assessments were obtained from 153 healthy controls (HC), 187 relapsing-remitting (RRMS), and 91 progressive MS (PMS) patients. AcAc, BHB, and acetone were measured using proton nuclear magnetic resonance spectroscopy. Indices of inflammatory vulnerability (IVX), metabolic malnutrition (MMX), and metabolic vulnerability (MVX) were computed from the NMR profiles. Cholesterol, apolipoprotein, lipid peroxidation, and antioxidant profiles were obtained. Regression analysis adjusted for age, sex, body mass index, and HC, RRMS, or PMS disease status. Results: AcAc and BHB levels were greater in MS compared to HC. BHB and ketone bodies were positively associated with disability on the MS Severity Scale and ambulation time. BHB was positively associated with IVX, MMX, and MVX. AcAc was positively associated with MMX and negatively associated with IVX and MVX. Total ketone body concentration was positively associated with MMX and MVX. BHB and AcAc levels were negatively associated with the amino acids alanine, valine, and leucine. Conclusions: Ketone bodies are associated with inflammatory vulnerability, metabolic vulnerability, and ambulatory disability measures in MS.

Keywords:  acetoacetate; antioxidant defense; beta-hydroxybutyrate; ketone bodies; lipid peroxidation; metabolomics; multiple sclerosis

DOI:  https://doi.org/10.3390/nu17040640
Nutrients. 2025 Feb 13. pii: 663. [Epub ahead of print]17(4):

The Influence of Physical Exercise, Ketogenic Diet, and Time-Restricted Eating on De Novo Lipogenesis: A Narrative Review.

Antonio Paoli.

  De novo lipogenesis (DNL) is a metabolic pathway that converts carbohydrates into fatty acids, primarily occurring in the liver and, to a lesser extent, in adipose tissue. While hepatic DNL is highly responsive to dietary carbohydrate intake and regulated by insulin via transcription factors like SREBP-1c, adipose DNL is more modest and less sensitive to dietary overfeeding. Dysregulated DNL contributes to metabolic disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD). Lifestyle interventions, such as physical exercise, ketogenic diets, and time-restricted eating (TRE) offer promising strategies to regulate DNL and improve metabolic health. Physical exercise enhances glucose uptake in muscles, reduces insulin levels, and promotes lipid oxidation, thereby suppressing hepatic DNL. Endurance and resistance training also improve mitochondrial function, further mitigating hepatic triglyceride accumulation. Ketogenic diets shift energy metabolism toward fatty acid oxidation and ketogenesis, lower insulin, and directly downregulate lipogenic enzyme activity in the liver. TRE aligns feeding with circadian rhythms by optimizing AMP-activated protein kinase (AMPK) activation during fasting periods, which suppresses DNL and enhances lipid metabolism. The combined effects of these interventions demonstrate significant potential for improving lipid profiles, reducing hepatic triglycerides, and preventing lipotoxicity. By addressing the distinct roles of the liver and adipose DNL, these strategies target systemic and localized lipid metabolism dysregulation. Although further research is needed to fully understand their long-term impact, these findings highlight the transformative potential of integrating these approaches into clinical practice to manage metabolic disorders and their associated complications.

Keywords:  MASLD; NALFD; adipose tissue; endurance training; fat metabolism; intermittent fasting; ketone bodies; liposynthesis; liver

DOI:  https://doi.org/10.3390/nu17040663
Med Sci Sports Exerc. 2025 Feb 25.

Advanced Footwear Technology, but not Acute Ingestion of a Ketone Monoester, Improves Running Economy in Middle- and Long-Distance Runners.

Aidan J Brady, Megan B Moynagh, Simon Devenney, Brendan Egan.

PURPOSE: This study examined the separate and combined effects of advanced footwear technology (AFT) and acute ingestion of a ketone monoester on running economy (RE), time-to-exhaustion (TTE), and other metabolic and cardiorespiratory parameters.
METHODS: In a four-condition, placebo-controlled, randomized crossover design, 18 middle- and long-distance runners (male/female, 10/8, V̇O2peak: 59.4 ± 7.2 mL·kg-1·min-1) completed five 8 min stages of submaximal running (male: 10-14 km·h-1; female: 9-13 km·h-1) on a motorized treadmill, immediately followed by a ramp test to volitional exhaustion. Participants consumed 500 mL of either a 10% carbohydrate solution (CHO) or 500 mg·kg-1 body mass of an (R)-3-hydroxybutyl (R)-3-hydroxybutyrate ketone monoester with flavored water (KME) 20 min before exercise, and an additional 300 mL of the 10% carbohydrate solution or 250 mg·kg-1 body mass of KME during exercise, while wearing either Nike Pegasus Turbo (PEG) or Nike ZoomX Vaporfly Next% 3 (VAP) running shoes. The four randomized conditions were PEG+CHO, PEG+KME, VAP + CHO, and VAP + KME.
RESULTS: RE was significantly improved during the third and fourth submaximal running stages in VAP + CHO and VAP + KME compared to PEG+CHO and PEG+KME (all P < 0.05; ES = 0.53-0.84). RE was also improved during the fifth submaximal running stage in VAP + KME compared to PEG+CHO, and in VAP + CHO and VAP + KME compared to PEG+KME (all P < 0.05; ES = 0.56-0.66). No differences in RE were found between CHO and KME conditions. TTE was significantly longer in VAP + CHO (381 ± 125 s) than PEG+CHO (356 ± 140 s; ES = 0.18, P = 0.023) and PEG+KME (329 ± 131 s, ES = 0.40, P < 0.001) and in VAP + KME (375 ± 125 s) than PEG+KME (ES = 0.35, P < 0.001).
CONCLUSIONS: AFT, but not the acute ingestion of a ketone monoester, improved the RE of trained male and female middle- and long-distance runners at submaximal running speeds.

DOI: https://doi.org/10.1249/MSS.0000000000003682
Res Sq. 2025 Feb 14. pii: rs.3.rs-5961609. [Epub ahead of print]

A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity.

Martin Picard, Anna Monzel, Jack Devine, Darshana Kapri, Jose Enriquez, Caroline Trumpff.

Mitochondria are a diverse family of organelles that specialize to accomplish complimentary functions 1-3. All mitochondria share general features, but not all mitochondria are created equal 4.Here we develop a quantitative pipeline to define the degree of molecular specialization among different mitochondrial phenotypes - or mitotypes. By distilling hundreds of validated mitochondrial genes/proteins into 149 biologically interpretable MitoPathway scores (MitoCarta 3.0 5) the simple mitotyping pipeline allows investigators to quantify and interpret mitochondrial diversity and plasticity from transcriptomics or proteomics data across a variety of natural and experimental contexts. We show that mouse and human multi-organ mitotypes segregate along two main axes of mitochondrial specialization, contrasting anabolic (liver) and catabolic (brain) tissues. In cultured primary human fibroblasts exhibiting robust time-dependent and treatment-induced metabolic plasticity 6-8, we demonstrate how the mitotype of a given cell type recalibrates i) over time in parallel with hallmarks of aging, and ii) in response to genetic, pharmacological, and metabolic perturbations. Investigators can now use MitotypeExplorer.org and the associated code to visualize, quantify and interpret the multivariate space of mitochondrial biology.

DOI: https://doi.org/10.21203/rs.3.rs-5961609/v1
BJPsych Open. 2025 Feb 25. 11(2): e34

A pilot study of a ketogenic diet in bipolar disorder: clinical, metabolic and magnetic resonance spectroscopy findings.

Iain H Campbell, Nicole Needham, Helen Grossi, Ivana Kamenska, Saturnino Luz, Shane Sheehan, Gerard Thompson, Michael J Thrippleton, Melissa C Gibbs, Joana Leitao, Tessa Moses, Karl Burgess, Benjamin P Rigby, Sharon A Simpson, Emma McIntosh, Rachel Brown, Ben Meadowcroft, Frances Creasy, Maja Mitchell-Grigorjeva, John Norrie, Ailsa McLellan, Cheryl Fisher, Tomasz Zieliński, Giulia Gaggioni, Harry Campbell, Daniel J Smith.

   BACKGROUND: Preliminary evidence suggests that a ketogenic diet may be effective for bipolar disorder.
AIMS: To assess the impact of a ketogenic diet in bipolar disorder on clinical, metabolic and magnetic resonance spectroscopy outcomes.
METHOD: Euthymic individuals with bipolar disorder (N = 27) were recruited to a 6- to 8-week single-arm open pilot study of a modified ketogenic diet. Clinical, metabolic and MRS measures were assessed before and after the intervention.
RESULTS: Of 27 recruited participants, 26 began and 20 completed the ketogenic diet. For participants completing the intervention, mean body weight fell by 4.2 kg (P < 0.001), mean body mass index fell by 1.5 kg/m2 (P < 0.001) and mean systolic blood pressure fell by 7.4 mmHg (P < 0.041). The euthymic participants had average baseline and follow-up assessments consistent with them being in the euthymic range with no statistically significant changes in Affective Lability Scale-18, Beck Depression Inventory and Young Mania Rating Scale. In participants providing reliable daily ecological momentary assessment data (n = 14), there was a positive correlation between daily ketone levels and self-rated mood (r = 0.21, P < 0.001) and energy (r = 0.19 P < 0.001), and an inverse correlation between ketone levels and both impulsivity (r = -0.30, P < 0.001) and anxiety (r = -0.19, P < 0.001). From the MRS measurements, brain glutamate plus glutamine concentration decreased by 11.6% in the anterior cingulate cortex (P = 0.025) and fell by 13.6% in the posterior cingulate cortex (P = <0.001).
CONCLUSIONS: These findings suggest that a ketogenic diet may be clinically useful in bipolar disorder, for both mental health and metabolic outcomes. Replication and randomised controlled trials are now warranted.

Keywords:  Bipolar disorder; ketogenic diet; ketosis; magnetic resonance spectroscopy; metabolic psychiatry

DOI:  https://doi.org/10.1192/bjo.2024.841
Diabetes Obes Metab. 2025 Feb 28.

Carnitine supplementation improves insulin sensitivity and skeletal muscle acetylcarnitine formation in patients with type 2 diabetes.

Yvonne M H Op den Kamp-Bruls, Yvo J M Op den Kamp, Pandichelvam Veeraiah, Ruben Zapata Perez, Esther Phielix, Bas Havekes, Gert Schaart, Esther Kornips, Bart R B Berendsen, Ashraf Virmani, Joachim E Wildberger, Riekelt H Houtkooper, Matthijs K C Hesselink, Patrick Schrauwen, Vera B Schrauwen-Hinderling.

   AIM/HYPOTHESIS: Recently, we reported that increasing free carnitine availability resulted in elevated skeletal muscle acetylcarnitine concentrations and restored metabolic flexibility in individuals who have impaired glucose tolerance. Metabolic flexibility is defined as the capacity to switch from predominantly fat oxidation while fasted to carbohydrate oxidation while insulin stimulated. Here we investigated if carnitine supplementation enhances the capacity of skeletal muscle to form acetylcarnitine and thereby improves insulin sensitivity and glucose homeostasis in patients with type 2 diabetes (T2DM).
METHODS: Thirty-two patients followed a 12-week L-carnitine treatment (2970 mg/day, orally). Insulin sensitivity was assessed by a two-step hyperinsulinemic-euglycemic clamp. In vivo skeletal muscle acetylcarnitine concentrations at rest and post-exercise (30 min, 70% Wmax) and intrahepatic lipid content (IHL) were determined by proton magnetic resonance spectroscopy (1H-MRS). All measurements were performed before and after 12 weeks of carnitine supplementation.
RESULTS: Compliance with the carnitine supplementation was good (as indicated by increased plasma-free carnitine levels (p < 0.01) and pill count (97.1 ± 0.7%)). Insulin-induced suppression of endogenous glucose production (31.9 ± 2.9 vs. 39.9 ± 3.2%, p = 0.020) and peripheral insulin sensitivity (Δ rate of glucose disappearance (ΔRd): 10.53 ± 1.85 vs. 13.83 ± 2.02 μmol/kg/min, p = 0.005) improved after supplementation. Resting (1.18 ± 0.13 vs. 1.54 ± 0.17 mmol/kgww, p = 0.008) and post-exercise (3.70 ± 0.22 vs. 4.53 ± 0.30 mmol/kgww, p < 0.001) skeletal muscle acetylcarnitine concentrations were both elevated after carnitine supplementation. Plasma glucose (p = 0.083) and IHL (p = 0.098) tended to be reduced after carnitine supplementation.
CONCLUSION: Carnitine supplementation improved insulin sensitivity and tended to lower IHL and fasting plasma glucose levels in patients with type 2 diabetes. Furthermore, carnitine supplementation increased acetylcarnitine concentration in muscle, which may underlie the beneficial effect on insulin sensitivity.

Keywords:  acetylcarnitine; carnitine supplementation; hyperinsulinemic‐euglycemic clamp; insulin sensitivity; intrahepatic lipid content; magnetic resonance spectroscopy; type 2 diabetes

DOI:  https://doi.org/10.1111/dom.16298
J Nutr Biochem. 2025 Feb 20. pii: S0955-2863(25)00036-1. [Epub ahead of print] 109873

Unsaturated Fatty Acids Enhance Mitochondrial Function and PGC1-α Expression in Brown Adipose Tissue of Obese Mice on a Low-Carbohydrate Diet.

Yasmin A M Ferreira, Aline B Santamarina, Laís V Mennitti, Esther A de Souza, Carla M Prado, Luciana P Pisani.

   INTRODUCTION: Brown adipose tissue (BAT) exhibits greater resilience against inflammation compared to white adipose tissue. However, chronic consumption of a high-fat diet can render brown adipocytes vulnerable to pro-inflammatory conditions, leading to a decline in their thermogenic capacity and subsequent dysfunction. The analysis of the effects of type fatty acids intake must be important in the context of the dietary pattern and obesity.
OBJECTIVES: This study aims to investigate the impact of a low-carbohydrate/high-fat diet, enriched with different types of fatty acids, on mitochondrial activity on brown adipose tissue in obese mice.
METHODS: Male mice were allocated into different dietary groups: a control diet (CTL), and a high-fat diet (HFD) for a duration of 10 weeks to induce obesity. Subsequently, the HFD group was subdivided into the following categories for an additional 6 weeks: HFD with a low carbohydrate content enriched with saturated fatty acids; HFD with a low carbohydrate content enriched with fish oil; HFD with a low carbohydrate content enriched with soybean oil; and HFD with a low carbohydrate content enriched with olive oil.
RESULTS: The findings indicated that in comparison to a low-carbohydrate diet rich in saturated fats, diets rich in unsaturated fatty acids-particularly omega-6 (n-6) and omega-9 (n-9)-resulted in elevated expression of UCP1, a marker of BAT activity. Moreover, there was an increase in the expression of PGC1-α, a protein involved in mitochondrial biogenesis, and enhanced functionality of the oxidative phosphorylation system within BAT mitochondria. These results suggest that n-6 and n-9 fatty acids may confer greater benefits to BAT functionality than saturated fats within the context of a low-carbohydrate diet. Therefore, this study revealed some molecular components that mediate BAT mitochondria function influenced by different fatty acids in a low carbohydrate diet, making it an important therapeutic target in obesity.

Keywords:  Adipose tissue; fatty acids; low-carbohydrate diet; mitochondrial complex; obesity

DOI:  https://doi.org/10.1016/j.jnutbio.2025.109873
J Appl Physiol (1985). 2025 Feb 27.

Oral contraceptive pill phase does not influence muscle protein synthesis or myofibrillar proteolysis at rest or in response to resistance exercise.

Lauren M Colenso-Semple, James McKendry, Changhyun Lim, Philip J Atherton, Daniel J Wilkinson, K Smith, Stuart M Phillips.

  There is speculation that oral contraceptive pill (OCP) use affects skeletal muscle biology and protein turnover in response to resistance exercise; however, research in this area is scarce. We aimed to assess, using stable isotope tracers and skeletal muscle biopsies, how second-generation OCP phase affected muscle protein synthesis and whole-body proteolysis. Participants (n=12) completed two 6-day study phases in a randomized order: an active pill phase (Active; week two of a monthly active OCP cycle) and an inactive pill phase (Inactive; final week of a monthly OCP cycle). Participants performed unilateral resistance exercise in each study phase, exercising the contralateral leg in the opposite phase in a randomized, counterbalanced order. The Active phase myofibrillar protein synthesis (MPS) rates were 1.44 ± 0.14 %•d-1 in the control leg and 1.64 ± 0.15 %•d-1 in the exercise leg (p < 0.001). The Inactive phase MPS rates were 1.49 ± 0.12 %•d-1 %/d in the control leg and 1.71 ± 0.16 %•d-1 in the exercise leg (p < 0.001), with no interaction between phases (p = 0.63). There was no significant effect of OCP phase on whole-body myofibrillar proteolytic rate (active phase k = 0.018 ± 0.01; inactive phase k = 0.018 ± 0.006; p = 0.55). Skeletal muscle remains equally as responsive, in terms of stimulation of MPS, during Active and Inactive OCP phases; hence, our data does not support a pro-anabolic or catabolic, based on myofibrillar proteolysis, effect of OCP phase on skeletal muscle in females.

Keywords:  Anabolism; Female; Protein turnover; Resistance exercise

DOI:  https://doi.org/10.1152/japplphysiol.00035.2025
Eur J Clin Nutr. 2025 Feb 26.

The effects of high protein intakes during energy restriction on body composition, energy metabolism and physical performance in recreational athletes.

Mikael F Kanaan, Samir Nait-Yahia, Éric Doucet.

BACKGROUND: Athletes employ weight loss practices to lower body fat and maintain fat-free mass (FFM). High protein diets have been shown to produce greater fat loss and retention of lean mass during periods of energy restriction (ER) in sedentary individuals with obesity, but less is known about the effects of high protein diets in trained individuals during ER. Although current recommendations for protein intake in active individuals are 1.2-1.7 g/kg, it is unclear whether higher intakes are necessary to maximize FFM retention and maximize physical performance in athletes undergoing periods of ER.
OBJECTIVE: Determine whether high protein intakes could maximize FFM retention and physical performance in trained individuals after a period of ER.
METHODS: Twenty-one college aged athletes underwent a 6-week 25% ER + 3-day full body resistance training. Participants were randomly assigned to a low (~1.2 g/kg), moderate (~1.6 g/kg) or high (~2.2 g/kg) protein intake. Baseline and post-intervention outcomes: Dual X-ray absorptiometry, isotopic water dilution, indirect calorimetry, dietary records and strength based physical testing.
RESULTS: Significant reductions in body mass (p = 0.047) and fat mass (p = 0.04) with simultaneous increases in FFM (p = 0.037) were noted for all groups, with no protein intake effect. Significant increases in physical performance outcomes (5RM strength) were noted for most measures (p < 0.05).
CONCLUSION: Current protein intake recommendations of 1.2-1.7 g/kg appear sufficient for most athletes even during periods of ER to maintain FFM and physical performance.

DOI: https://doi.org/10.1038/s41430-025-01585-2
Trends Cell Biol. 2025 Feb 25. pii: S0962-8924(25)00038-8. [Epub ahead of print]

Mitochondrial substrate oxidation regulates distinct cell differentiation outcomes.

Woo Yong Park, Claudia Montufar, Elma Zaganjor.

  Mitochondrial metabolism, signaling, and dynamics are key regulators of cell fate. While glycolysis supports stemness, mitochondrial expansion and oxidative phosphorylation (OXPHOS) facilitate differentiation. This forum presents emerging evidence that the type of substrate, whether amino acids, carbohydrates, or fatty acids, oxidized by mitochondria significantly influences differentiation outcomes.

Keywords:  OXPHOS; amino acids; differentiation; fatty acids; glucose; mitochondria

DOI:  https://doi.org/10.1016/j.tcb.2025.02.004
PLoS One. 2025 ;20(2): e0318782

Transcriptomic adaptation of skeletal muscle in response to MICT and HIIT exercise modalities.

Weihao Hong, Yisheng Luan, Jianrong Zheng, Yingzhe Xiong, Bing Zhang, Yixuan Ma.

Skeletal muscle exhibits remarkable plasticity in response to diverse stimuli, with exercise serving as a potent trigger. Varied exercise modalities, including moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT), induce distinct structural and functional adaptations on skeletal muscle. However, the underlying molecular mechanisms governing these adaptations remain poorly understood. In this study, we utilized RNA-seq to characterize the transcriptomic profile of murine gastrocnemius muscle following 8-week treadmill-based MICT (M group) and HIIT (H group). A total of 1052 DEGs were screened in H vs. M. Among the top 10 significant DEGs, Foxo1 and Myod1 are closely related to muscular physiology. Through KEGG pathway analysis, distinct adaptations were primarily identified in the FoxO, MAPK, and PI3K-AKT pathways. By analyzing the expression of myokines, a significantly higher Igf-1 expression level was observed in the M group compared to the H group. Therefore, IGF-1, a well-known upstream regulator of both the PI3K-AKT-FoxO and MAPK pathways, might drive distinct muscle adaptations through variations in Igf-1 expression induced by these two exercise modalities.

DOI: https://doi.org/10.1371/journal.pone.0318782
Physiol Rep. 2025 Mar;13(5): e70242

Cardiac energy metabolism is decreased in male volunteers with prediabetes and does not normalize during the day.

Vera H W de Wit-Verheggen, Jakob Wefers, Carlijn M E Remie, Patrick Schrauwen, Vera B Schrauwen-Hinderling, Tineke van de Weijer.

  Type 2 diabetes mellitus is characterized by a low cardiac energy status (PCr/ATP ratio), but it is unknown whether this also applies to prediabetes. Since PCr/ATP is correlated with elevated free fatty acids (FFA), a potentially lower PCr/ATP might be secondary to elevated FFA. To investigate this, we determined PCr/ATP and FFA levels in volunteers with prediabetes at two time-points during the day. Eight male volunteers with prediabetes underwent a MRI/MRS scan to determine left ventricular ejection fraction (LVEF) and PCr/ATP ratio at 7 am and at 5 pm. For reference, these results were compared to eight non-insulin resistant overweight or obese volunteers. Myocardial energy status was lower in the volunteers with prediabetes (PCr/ATP 1.03 ± 0.08) compared to non-insulin resistant overweight or obese volunteers (PCr/ATP 1.22 ± 0.04, p < 0.05), but FFA were not significantly different between groups. LVEF was similar in the volunteers with prediabetes compared to healthy overweight and obese volunteers (p = 0.23). Volunteers with prediabetes have a lower myocardial energy status in the morning compared to healthy overweight and obese volunteers, while cardiac function remained normal. In addition, no differences between morning and evening measurements of cardiac energy status and function were found.

Keywords:  PCr/ATP; cardiac energy status; prediabetes

DOI:  https://doi.org/10.14814/phy2.70242
Nature. 2025 Feb;638(8052): 874-876

How quickly are you ageing? What molecular 'clocks' can tell you about your health.

Heidi Ledford.



Keywords:  Ageing; Epigenetics; Medical research

DOI:  https://doi.org/10.1038/d41586-025-00566-6
J Exp Biol. 2025 Feb 27. pii: jeb.249704. [Epub ahead of print]

Mitochondrial respiration capacity impacts gill tissue regeneration in Atlantic salmon.

Ensiyeh Ghanizadeh-Kazerouni, Benjamin Negrete J, Simon R M Jones, Mark D Fast, Colin J Brauner.

  Gill regeneration in fish varies inter and intra-specifically. The latter may be associated with myriad factors including capacity of energy metabolism. This study investigated whether mitochondrial respiration capacity influences the degree of gill regeneration, and features of mitochondria in regenerated tissue by feeding fish an experimental diet aimed at modulating mitochondrial efficiency. Fish reared on control and experimental diet were subjected to 50% filament resection on a subset of filaments on the ventral and dorsal regions of the first gill arch. Mitochondrial respiration and citrate synthase activity (CSA) were measured in the resected tips of filaments (week-0) and then in the regenerated tissue at week-20 post-resection. The degree of filament regeneration was measured at week-20 post-resection (week-20). The experimental diet reduced CSA and respiratory control ratio (RCR), and increased proton leak at week-0 which was associated with a 30% reduction in tissue regeneration compared to fish on standard diet. While CSA increased in the regenerated tissue at week-20, there was a decline in state 3 respiration, proton leak, complex IV activity, and RCR as compared to week-0 irrespective of diet. Overall, mitochondrial respiration efficiency at week-0 was positively correlated with the degree of subsequent gill tissue regeneration. Additionally, state 3 respiration and proton leak at week-20 were positively correlated with tissue regeneration, whereas CSA exhibited a negative relationship. Our results indicate that capacity of mitochondrial respiration may at least partially explain the inter-individual variations in tissue regeneration, but mitochondrial function in the regenerating tissue may be limited.

Keywords:  Atlantic salmon; Citrate synthase activity; Gill tissue regeneration; Mitochondrial respiratory capacity; Proton leak

DOI:  https://doi.org/10.1242/jeb.249704
ESC Heart Fail. 2025 Feb 28.

Effects of exercise modalities on physical function and quality of life in patients with heart failure: A systematic review and network meta-analysis.

Jiang-Ying Li, Lu Chen, Qiu-Chen Wang, Jian Zhu, Zhen-Qing Ren, Li-Chun Wang.

   AIMS: This study aimed to evaluate the effects of various exercise modalities on physical function and quality of life in individuals with heart failure and to identify the most effective approaches.
METHODS AND RESULTS: A network meta-analysis was conducted by searching PubMed, Embase and the Cochrane Library databases. Random-effects meta-analyses were performed to estimate mean differences (MD) and 95% confidence intervals (CI). A total of 60 randomized controlled trials, comprising 3261 participants, were included in the analysis. Yoga was associated with the greatest improvement in left ventricular ejection fraction (P-score = 0.91, MD: 0.90; 95% CI: 0.42 to 1.38) and the most significant reduction in serum natriuretic peptide levels (P-score = 0.965, MD: -1.46; 95% CI: -1.88 to -1.04). Interval training demonstrated superior effectiveness in increasing the 6-min walk distance (6MWD) (P-score = 0.873, MD: 113.01; 95% CI: 28.55 to 197.47). Combined aerobic and resistance training (AT + RT) showed the greatest benefits in enhancing peak oxygen uptake (VO2peak) (P-score = 0.829, MD: 3.68; 95% CI: 2.23 to 5.13). High-intensity interval training combined with inspiratory muscle training (HIIT + IMT) yielded the most significant improvements in quality of life (P-score = 0.871, MD: -19.28; 95% CI: -26.42 to -12.14) and the greatest reduction in dyspnea (P-score = 0.804, MD: -1.58; 95% CI: -2.64 to -0.52).
CONCLUSIONS: Current evidence suggests that yoga, interval training, AT + RT, and HIIT + IMT significantly enhance physical function and quality of life in individuals with heart failure, with each modality exhibiting distinct advantages. Further high-quality studies are warranted to confirm these findings and refine exercise prescriptions for this population.

Keywords:  Exercise modalities; Heart failure; Network meta‐analysis; Physical function; Quality of life

DOI:  https://doi.org/10.1002/ehf2.15256
Nutrients. 2025 Feb 11. pii: 646. [Epub ahead of print]17(4):

The Role of Dairy in Human Nutrition: Myths and Realities.

Laura Sanjulián, Salvador Fernández-Rico, Nerea González-Rodríguez, Alberto Cepeda, José Manuel Miranda, Cristina Fente, Alexandre Lamas, Patricia Regal.

  Milk is a highly complex food that contains all the nutrients necessary for the development of mammalian offspring. For millennia, humans have included milk and milk products as major components of their diet. However, the effect of the consumption of dairy products on health has been a concern in recent years in terms of myths and realities. This review briefly describes the composition of bovine milk, the positive and negative effects that have been related to dairy products, and those aspects where the scientific evidence is still inconclusive. In addition to being nutritional, dairy products are a source of bioactive peptides, prebiotics and probiotics, fatty acids such as CLA, and fat globule membranes or have a protective effect against certain diseases. Negative effects include milk protein allergy or lactose intolerance. The effects of dairy products on certain cancers, such as prostate cancer, and their role in type II diabetes mellitus or weight gain are still inconclusive. Although the role of dairy products in cardiovascular risk is still inconclusive, recent meta-analyses have shown that dairy products may have a protective effect.

Keywords:  cow milk; dairy; diet; fermented milk; human health; probiotics

DOI:  https://doi.org/10.3390/nu17040646
Trends Cell Biol. 2025 Feb 25. pii: S0962-8924(25)00036-4. [Epub ahead of print]

ER-mitochondria contact sites: a refuge for mitochondrial mRNAs under ER stress.

Philippe Pihán, Lisa M Ellerby, Claudio Hetz.

  Tight mitochondria-endoplasmic reticulum (ER) contacts (MERCS) play essential roles in cellular homeostasis. Brar et al. reveal a novel mechanism where mitochondrial mRNAs escape global translational repression at novel context-specific MERCS during ER stress, uncovering spatially regulated translation as a critical adaptive strategy to cope with cellular stress.

Keywords:  ATAD3A; PERK; endoplasmic reticulum stress; mitochondria–ER contact sites (MERCS); spatial translation regulation

DOI:  https://doi.org/10.1016/j.tcb.2025.02.002
Antioxidants (Basel). 2025 Jan 25. pii: 143. [Epub ahead of print]14(2):

MCC950 Reduces the Anxiodepressive-like Behaviors and Memory Deficits Related to Paclitaxel-Induced Peripheral Neuropathy in Mice.

Ignacio Martínez-Martel, Sylmara Esther Negrini-Ferrari, Olga Pol.

  Chemotherapy-induced peripheral neuropathy and the accompanying affective disorders are serious side effects, and their resolution is not guaranteed. Oxidative stress and elevated levels of Nod-like receptor protein 3 (NLRP3) have been detected in the peripheral and central nervous systems of animals with neuropathic pain provoked by several antineoplastic drugs, such as paclitaxel (PTX). Several studies have further indicated that NLRP3 inflammasome inhibition could be an approach for treating chronic pain, but its impact on the anxiodepressive-like behaviors and memory deficits related to PTX-provoked neuropathy has not yet been investigated. MCC950 is a potent and specific inhibitor of the NLRP3 pathway that acts through inhibiting NLRP3 activation and inflammasome formation. We hypothesized that the administration of MCC950 could alleviate the affective and cognitive disorders accompanying PTX-provoked neuropathy. Using male C57BL/6 mice, we assessed the effects of MCC950 on the mechanical and thermal allodynia, anxiodepressive-like behavior, and memory deficits incited by this taxane. The results indicated that the intraperitoneal administration of 10 mg/kg of MCC950 twice daily for three consecutive days fully reversed the PTX-induced mechanical and thermal allodynia. This treatment also completely attenuated the anxiolytic (p < 0.004) and depressive-like behaviors (p < 0.022) and memory deficits (novel object recognition test; p < 0.0018) incited by PTX. These actions were mainly achieved through blocking NLRP3 inflammasome activation in the sciatic nerve, amygdala, and hippocampus, and oxidative stress in the amygdala and hippocampus. MCC950 also normalized the p-ERK 1/2 overexpression in the sciatic nerve and apoptotic responses in the sciatic nerve and the amygdala. This study suggests that MCC950 might be a promising treatment for PTX-induced mental illnesses and neuropathy.

Keywords:  MCC950; NLRP3 inflammasome; anxiety; depression; memory; neuropathic pain; oxidative stress; paclitaxel

DOI:  https://doi.org/10.3390/antiox14020143
Behav Sci (Basel). 2025 Feb 18. pii: 232. [Epub ahead of print]15(2):

Physical Exercise and Sleep Quality Among Chinese College Students: The Mediating Role of Self-Control and the Moderating Role of Mindfulness.

Xiaopeng Li, Chengli Xu, Wanyi Chen, Jing Tian.

  Although a few studies have examined the relationship between physical exercise and sleep quality, the underlying mechanisms of this association remain unclear. This study aims to investigate how and under what conditions physical exercise can promote the sleep quality among Chinese college students, with a focus on how self-control mediates and mindfulness moderates this relationship. Data were collected through convenient sampling from five universities in China, with a total of 1028 college students aged 16 to 29 participating in the study. Participants were recruited to complete the self-report questionnaires measuring their physical exercise, self-control, sleep quality and mindfulness. Results showed that physical exercise significantly and positively predicts sleep quality among Chinese college students. Further moderated mediation analyses indicated that self-control plays a significant mediating role, while mindfulness plays a moderating role in this relationship. Additionally, simple slopes analyses found that the moderating effect of mindfulness is more pronounced among individuals with lower levels of mindfulness compared to those with higher levels. The findings suggest that physical exercise can enhance sleep quality by improving self-control. Furthermore, physical exercise has a beneficial impact on self-control and sleep quality among college students with low mindfulness, while mindfulness itself exerts a distinct positive influence among those with high mindfulness.

Keywords:  mindfulness; physical exercise; self-control; sleep quality

DOI:  https://doi.org/10.3390/bs15020232
Cells. 2025 Feb 11. pii: 257. [Epub ahead of print]14(4):

How the Topology of the Mitochondrial Inner Membrane Modulates ATP Production.

Raquel Adams, Nasrin Afzal, Mohsin Saleet Jafri, Carmen A Mannella.

  Cells in heart muscle need to generate ATP at or near peak capacity to meet their energy demands. Over 90% of this ATP comes from mitochondria, strategically located near myofibrils and densely packed with cristae to concentrate ATP generation per unit volume. However, a consequence of dense inner membrane (IM) packing is that restricted metabolite diffusion inside mitochondria may limit ATP production. Under physiological conditions, the flux of ATP synthase is set by ADP levels in the matrix, which in turn depends on diffusion-dependent concentration of ADP inside cristae. Computer simulations show how ADP diffusion and consequently rates of ATP synthesis are modulated by IM topology, in particular (i) number, size, and positioning of crista junctions that connect cristae to the IM boundary region, and (ii) branching of cristae. Predictions are compared with the actual IM topology of a cardiomyocyte mitochondrion in which cristae vary systematically in length and morphology. The analysis indicates that this IM topology decreases but does not eliminate the "diffusion penalty" on ATP output. It is proposed that IM topology normally attenuates mitochondrial ATP output under conditions of low workload and can be regulated by the cell to better match ATP supply to demand.

Keywords:  ATP synthesis; cristae; electron tomography; membrane topology; metabolic modeling; metabolite diffusion; mitochondria

DOI:  https://doi.org/10.3390/cells14040257