bims-mifefi Biomed News
on Mitochondria and female physiology
Issue of 2024–02–18
twelve papers selected by
Kayla Vandiver, East Carolina University



  1. Am J Physiol Cell Physiol. 2024 Feb 12.
      Dysregulation of skeletal muscle morphology and metabolism is associated with chronic diseases such as obesity and type 2 diabetes. The enzyme glycogen synthase kinase 3 (GSK3) is highly involved in skeletal muscle physiology and metabolism, acting as a negative regulator of muscle size, strength, adaptive thermogenesis, and glucose homeostasis. Correspondingly, we have shown that partial gene expression knockdown (~40%) of gsk3 specifically in skeletal muscle increases lean mass, reduces fat mass, and activates muscle-based adaptive thermogenesis via sarco(endo)plasmic reticulum Ca2+ (SERCA) uncoupling in male mice. However, the effects of partial GSK3 knockdown in female mice have yet to be investigated. Here, we examined the effects of muscle-specific GSK3 knockdown on body composition, muscle size and strength, and whole-body metabolism in female C57BL/6J mice. Our results show that GSK3 content is higher in the female soleus vs. the male soleus; however, there were no differences in the extensor digitorum longus (EDL). Furthermore, muscle-specific GSK3 knockdown did not alter body composition in female mice, nor did it alter daily energy expenditure, glucose/insulin tolerance, mitochondrial respiration, or the expression of the SERCA uncouplers sarcolipin and neuronatin. We also did not find any differences in soleus muscle size, strength, or fatigue resistance. In the EDL, we found an increase in cross-sectional area associated with an increase in absolute force production but there were no differences in fatigability. Therefore, our study highlights sex-differences in the response to genetic reduction of gsk3, with most of the effects previously observed in male mice being absent in females.
    Keywords:  Energy expenditure; Force production; Muscle; Thermogenesis
    DOI:  https://doi.org/10.1152/ajpcell.00398.2023
  2. Front Endocrinol (Lausanne). 2024 ;15 1356312
       Background: Postmenopausal women are more prone to develop muscle weakness, which is strongly associated with impairment of mitochondrial function in skeletal muscle. This study aimed to examine the impact of a passive exercise modality, whole-body vibration training (WBVT), on muscle mitochondrial function in ovariectomized (OVX) mice, in comparison with 17β-estradiol (E2) replacement.
    Methods: Female C57BL/6J mice were assigned to four groups: sham operation control group (Sham), ovariectomized group (OVX), OVX with E2 supplement group (OVX+E), and OVX with WBVT group (OVX+W). The estrous cycle, body weight, body composition, and muscle strength of the mice were monitored after the operation. Serum E2 level was assessed by enzyme-linked immunosorbent assay (ELISA). The ATP levels were determined using a luciferase-catalyzed bioluminescence assay. The activity of mitochondrial respiration chain complexes was evaluated using high-resolution respirometry (O2K). Expression levels of oxidative phosphorylation (OXPHOS), peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), and mitochondrial transcription factor A (TFAM) were detected using western blotting.
    Results: We observed decreased muscle strength and impaired mitochondrial function in the skeletal muscle of OVX mice. The vibration training alleviated these impairments as much as the E2 supplement. In addition, the vibration training was superior to the ovariectomy and the estradiol replacement regarding the protein expression of PGC-1α and TFAM.
    Conclusion: WBVT improves the OVX-induced decline in muscle strength and impairment of mitochondrial function in the skeletal muscle. This passive exercise strategy may be useful as an alternative to E2 replacement for preventing menopausal muscular weakness. Further studies are needed to understand the effects of WBVT on various physiological systems, and precautions should be taken when implementing it in patient treatment.
    Keywords:  17β-estradiol replacement; hormone replacement therapy; mitochondrial function; muscle weakness; ovariectomized mice; passive exercise; whole-body vibration training
    DOI:  https://doi.org/10.3389/fendo.2024.1356312
  3. J Appl Physiol (1985). 2024 Feb 15.
      Chronic alcohol intoxication decreases muscle strength/function and causes mitochondrial dysfunction. Aerobic exercise training improves mitochondrial oxidative capacity and increases muscle mass and strength. Presently, the impact of chronic alcohol on aerobic exercise-induced adaptations was investigated. Female C57BL/6Hsd mice were randomly assigned to one of 4 groups: control sedentary (CON SED; n=26), alcohol sedentary (ETOH SED; n=27), control exercise (CON EX; n=28), and alcohol exercise (ETOH EX; n=25). Exercise mice had running wheel access for 2hrs a day, 7 days a week. All mice were fed either control or alcohol-containing liquid diet. Grip strength testing and EchoMRI were performed before and after the interventions. After 6 weeks, hindlimb muscles were collected for molecular analyses. A subset of mice performed a treadmill run to fatigue (RTF), then abstained from alcohol for 2 weeks and repeated the RTF. Alcohol decreased lean mass and forelimb grip strength compared to control-fed mice. Alcohol blunted the exercise induced increase in muscle mass (plantaris and soleus), type IIa fiber percentage in the plantaris and run time to fatigue. Mitochondrial markers (Citrate synthase activity and Complex I-IV, COXIV and Cytochrome C protein expression), were increased with exercise regardless of ETOH in the gastrocnemius but not tibialis anterior muscle. Two-weeks of alcohol abstinence improved RTF time in ETOH EX but not in ETOH SED. While these data suggest alcohol impairs some exercise-induced adaptations in skeletal muscle, not all were negatively affected, indicating exercise may be a beneficial behavior even while consuming alcohol.
    Keywords:  alcohol; endurance performance; ethanol; mitochondria; wheel running
    DOI:  https://doi.org/10.1152/japplphysiol.00599.2023
  4. Front Physiol. 2023 ;14 1334766
      Background: A training program can stimulate physiological, anatomical, and performance adaptations, but these improvements can be partially or entirely reversed due to the cessation of habitual physical activity resulting from illness, injury, or other influencing factors. Purpose: To investigate the effects of detraining on cardiorespiratory, metabolic, hormonal, muscular adaptations, as well as short-term and long-term performance changes in endurance athletes. Methods: Eligible studies were sourced from databases and the library up until July 2023. Included studies considered endurance athletes as subjects and reported on detraining duration. Results: Total cessation of training leads to a decrease in VO2max due to reductions in both blood and plasma volume. Cardiac changes include decreases in left ventricular mass, size, and thickness, along with an increase in heart rate and blood pressure, ultimately resulting in reduced cardiac output and impaired performance. Metabolically, there are declines in lactate threshold and muscle glycogen, increased body weight, altered respiratory exchange ratio, and changes in power parameters. In the short term, there is a decrease in insulin sensitivity, while glucagon, growth hormone, and cortisol levels remain unchanged. Skeletal muscle experiences reductions in arterial-venous oxygen difference and glucose transporter-4. Implementing a partial reduction in training may help mitigate drastic losses in physiological and performance parameters, a consideration when transitioning between training seasons. Conclusion: There is a dearth of data investigating the detraining effects of training reduction/cessation among endurance athletes. Delving deeper into this topic may be useful for professionals and researchers to identify the optimal strategies to minimize these effects.
    Keywords:  deconditioning; detraining effect; endurance; training cessation; training reduction
    DOI:  https://doi.org/10.3389/fphys.2023.1334766
  5. Biosens Bioelectron. 2024 Feb 09. pii: S0956-5663(24)00128-3. [Epub ahead of print]251 116123
      Breast cancer lung metastases (BCLM) are a major cause of high mortality in patients. The shortage of therapeutic targets and rapid drug screening tools for BCLM is a major challenge at present. Mitochondrial autophagy, which involves the degradation of proteins associated with cancer cell aggressiveness, represents a possible therapeutic approach for the treatment of BCLM. Herein, four fluorescent biosensors with different alkyl chains were designed and synthesized to monitor mitochondrial autophagy. Among them, PMV-12 demonstrated the highest sensitivity to viscosity variance, the least impact on polarity, and the longest imaging time. The introduction of the C12-chain made PMV-12 anchored in the mitochondrial membrane without being disturbed by changes of the mitochondrial membrane potential (MMP), thereby achieving the long-term monitor in situ for mitochondrial autophagy. Mitochondria stained with PMV-12 induced swelling and viscosity increase after treating with apigenin, which indicated that apigenin is a potential mitochondrial autophagy inducer. Apigenin was subsequently verified to inhibit cancer cell invasion by 92%. Furthermore, PMV-12 could monitor the process of BCLM in vivo and evaluate the therapeutic effects of apigenin. This work provides a fluorescent tool for elucidating the role of mitochondrial autophagy in the BCLM process and for anti-metastatic drug development.
    Keywords:  Breast cancer metastasis; Fluorescence imaging; Long-term visualization; Mitochondrial autophagy
    DOI:  https://doi.org/10.1016/j.bios.2024.116123
  6. Med Sci Sports Exerc. 2024 Mar 01. 56(3): 499-510
       PURPOSE: Oral contraceptives (OCs) are commonly used by female athletes, but their effects on skeletal muscle are still poorly understood. We investigated if physically trained females using second-generation OCs differed from nonusers of OCs in the recovery of muscle function and muscle damage markers after repeated resistance exercise sessions.
    METHODS: We recruited 20 trained second-generation OC users and 20 trained nonusers to perform three strenuous resistance exercise sessions. Before, and 3, 24, and 48 h after exercise, blood samples were collected, and participants were evaluated for muscle soreness, maximal isometric and isokinetic muscle strength, vertical jump height, Wingate power performance, leg press strength, and intermittent recovery capacity (yo-yo test). All participants were provided with an energy-macronutrient-balanced diet during the experimental period.
    RESULTS: After resistance exercise, maximal isometric and isokinetic muscle strength, rate of force development, vertical jump height, and Wingate peak and average power were reduced, whereas markers of muscle damage were increased in both groups (P < 0.05). OC users experienced a greater reduction in isokinetic strength 3, 24, and 48 h after exercise compared with nonusers of OCs (interaction: P < 0.05). No other interactions were observed.
    CONCLUSIONS: We demonstrate that measures of muscle strength recovery after three strenuous resistance exercise sessions are comparable between trained females using second-generation OCs and nonusers of OCs. However, group differences were observed for isolated dynamic (isokinetic) muscle strength, suggesting a marginal benefit of not using OCs when accelerated recovery is needed.
    DOI:  https://doi.org/10.1249/MSS.0000000000003316
  7. Reprod Biol. 2024 Jan 30. pii: S1642-431X(24)00002-0. [Epub ahead of print]24(1): 100856
      Calorie restriction (CR) is an intervention that promotes longevity and preserves the ovarian reserve. Some studies have observed that the positive impacts of CR can be linked to restriction of protein (PR) and branched-chain amino acids (BCAAs) independent of calorie intake. The aim of this study was to compare the effects of protein and BCAA restriction to 30% CR on the ovarian reserve of female mice. For this, 3 month-old C57BL/6 female mice (n = 35) were randomized into four groups for four months dietary interventions including: control group (CTL; n = 8), 30% CR (CR; n = 9), protein restriction (PR; n = 9) and BCAA restriction (BCAAR; n = 9). Body mass gain, body composition, food intake, serum levels of BCAAs, ovarian reserve and estrous cyclicity were evaluated. We observed that CR, protein and BCAA restriction prevented weight gain and changed body composition compared to the CTL group. The BCAA restriction did not affect the ovarian reserve, while both PR and CR prevented activation of primordial follicles. This prevention occurred in PR group despite the lack of reduction of calorie intake compared to CTL group, and CR did not reduce protein intake in levels similar to the PR group. BCAA restriction resulted in increased calorie intake compared to CTL and PR mice, but only PR reduced serum BCAA levels compared to the CTL group. Our data indicates that PR has similar effects to CR on the ovarian reserve, whereas BCAA restriction alone did not affect it.
    Keywords:  BCAAs; Dietary interventions; Ovarian reserve; Primordial follicle
    DOI:  https://doi.org/10.1016/j.repbio.2024.100856
  8. Am J Physiol Endocrinol Metab. 2024 Feb 14.
      Exercise robustly increases the glucose demands of skeletal muscle. This demand is met not only by muscle glycogenolysis, but also by accelerated liver glucose production from hepatic glycogenolysis and gluconeogenesis to fuel mechanical work and prevent hypoglycemia during exercise. Hepatic gluconeogenesis during exercise is dependent on highly coordinated responses within and between muscle and liver. Specifically, exercise increases the rate at which gluconeogenic precursors such as pyruvate/lactate or amino acids are delivered from muscle to the liver, extracted by the liver, and channeled into glucose. Herein, we examined the effects of interrupting gluconeogenic efficiency and capacity on exercise performance by deleting hepatic mitochondrial pyruvate carrier 2 (MPC2) and/or alanine transaminase 2 (ALT2) in mice. We found that deletion of MPC2 or ALT2 alone did not significantly affect time to exhaustion or post-exercise glucose concentrations in treadmill exercise tests, but mice lacking both MPC2 and ALT2 in liver (DKO) reached exhaustion faster and exhibited lower circulating glucose during and after exercise. Use of ²H/¹³C metabolic flux analyses demonstrated that DKO mice exhibited lower endogenous glucose production owing to decreased glycogenolysis and gluconeogenesis at rest and during exercise. The decreased gluconeogenesis was accompanied by lower anaplerotic, cataplerotic, and TCA cycle fluxes. Collectively, these findings demonstrate that the transition of the liver to the gluconeogenic mode is critical for preventing hypoglycemia and sustaining performance during exercise. The results also illustrate the need for interorgan crosstalk during exercise as described by the Cahill and Cori cycles.
    Keywords:  alanine transaminase; exercise; gluconeogenesis; mitochondrial pyruvate carrier
    DOI:  https://doi.org/10.1152/ajpendo.00258.2023
  9. Horm Behav. 2023 Nov;pii: S0018-506X(23)00146-0. [Epub ahead of print]156 105448
      Gonadal hormone actions through androgen receptor (AR) and estrogen receptor alpha (ERα) regulate sex differences in hypothalamic-pituitary-adrenal (HPA) axis responsivity and stress-related behaviors. Here we tested whether corticotropin releasing factor (CRF) expressing neurons, which are widely known to regulate neuroendocrine and behavioral stress responses, co-express AR and ERα as a potential mechanism for gonadal hormone regulation of these responses. Using Crh-IRES-Cre::Ai9 reporter mice we report high co-localization of AR in CRF neurons within the medial preoptic area (MPOA), bed nucleus of the stria terminalis (BST), medial amygdala (MeA), and ventromedial hypothalamus (VMH), moderate levels within the central amygdala (CeA) and low levels in the paraventricular hypothalamus (PVN). Sex differences in CRF/AR co-expression were found in the principal nucleus of the BST (BSTmpl), CeA, MeA, and VMH (males>females). CRF co-localization with ERα was generally lower relative to AR co-localization. However, high co-expression was found within the MPOA, AVPV, and VMH, with moderate co-expression in the arcuate nucleus (ARC), BST, and MeA and low levels in the PVN and CeA. Sex differences in CRF/ERα co-localization were found in the BSTmpl and PVN (males>females). Finally, we assessed neural activation of CRF neurons in restraint-stressed mice and found greater CRF/c-Fos co-expression in females in the BSTmpl and periaqueductal gray, while co-expression was higher in males within the ARC and dorsal CA1. Given the known role of CRF in regulating behavioral stress responses and the HPA axis, AR/ERα co-expression and sex-specific activation of CRF cell groups indicate potential mechanisms for modulating sex differences in these functions.
    Keywords:  Androgen receptor; Corticotropin releasing factor; Estrogen receptor alpha; Mice; Sex differences
    DOI:  https://doi.org/10.1016/j.yhbeh.2023.105448
  10. Sports Med. 2024 Feb 12.
       BACKGROUND: In the last 5 years since our last systematic review, a significant number of articles have been published on the technical aspects of muscle near-infrared spectroscopy (NIRS), the interpretation of the signals and the benefits of using the NIRS technique to measure the physiological status of muscles and to determine the workload of working muscles.
    OBJECTIVES: Considering the consistent number of studies on the application of muscle oximetry in sports science published over the last 5 years, the objectives of this updated systematic review were to highlight the applications of muscle oximetry in the assessment of skeletal muscle oxidative performance in sports activities and to emphasize how this technology has been applied to exercise and training over the last 5 years. In addition, some recent instrumental developments will be briefly summarized.
    METHODS: Preferred Reporting Items for Systematic Reviews guidelines were followed in a systematic fashion to search, appraise and synthesize existing literature on this topic. Electronic databases such as Scopus, MEDLINE/PubMed and SPORTDiscus were searched from March 2017 up to March 2023. Potential inclusions were screened against eligibility criteria relating to recreationally trained to elite athletes, with or without training programmes, who must have assessed physiological variables monitored by commercial oximeters or NIRS instrumentation.
    RESULTS: Of the identified records, 191 studies regrouping 3435 participants, met the eligibility criteria. This systematic review highlighted a number of key findings in 37 domains of sport activities. Overall, NIRS information can be used as a meaningful marker of skeletal muscle oxidative capacity and can become one of the primary monitoring tools in practice in conjunction with, or in comparison with, heart rate or mechanical power indices in diverse exercise contexts and across different types of training and interventions.
    CONCLUSIONS: Although the feasibility and success of the use of muscle oximetry in sports science is well documented, there is still a need for further instrumental development to overcome current instrumental limitations. Longitudinal studies are urgently needed to strengthen the benefits of using muscle oximetry in sports science.
    DOI:  https://doi.org/10.1007/s40279-023-01987-x
  11. BMC Sports Sci Med Rehabil. 2024 Feb 12. 16(1): 45
       BACKGROUND: The primary aim of this study was to examine the relationship between maximal oxygen update (V̇O2max) and within-set fatigue and between-set recovery during resistance exercise in men and women.
    METHODS: We examined the relationship between V̇O2max and various indices of fatigue and recovery during parallel squats (3 sets, 90 s rest, 70% of 1RM to failure) and isokinetic knee extensions (3 × 10 maximal repetitions at 60 deg/s, 45 s rest) in 28 (age 27.0 ± 3.6 years) resistance-trained subjects (14 men and 14 women). We also examined whether there were sex differences in within-set fatigue and between-set recovery.
    RESULTS: V̇O2max was weakly related to recovery and fatigue in both men and women (range of P-values for V̇O2max as a covariate; 0.312-0.998, range of R-values, 0.005-0.604). There were no differences between the sexes in fatigue within a set for the squat, but men showed less within-set fatigue than women in the first set of the isokinetic knee extension exercise (~ 8% torque loss difference, main effect of sex P = 0.034). Regarding recovery between sets, men showed greater relative peak power (P = 0.016) and peak torque (P = 0.034) loss between sets in both exercises, respectively, compared to women. Women also tended to complete more repetitions than men (main effect of sex, P = 0.057). Loss of peak torque between sets in knee extension was evident in both absolute and relative (%) values in men but not in women.
    CONCLUSIONS: Our study suggests that aerobic capacity is weakly associated with within-set fatigue and between-set recovery in resistance training in both men and women. Women and men show comparable levels of within-set fatigue in the multi-joint squat, but women show more within-set fatigue during the single-joint isokinetic knee extension compared with men. In contrast, women recover better than men between sets in both exercises.
    Keywords:  Inter-set rest; Muscle fatigue; Sex differences; Strength training; V̇O2max
    DOI:  https://doi.org/10.1186/s13102-024-00830-8
  12. BMC Womens Health. 2024 Feb 12. 24(1): 117
       PURPOSE: This study aimed to investigate the difference in absolute and fat free mass (FFM)-adjusted resting energy expenditure (mREE) and body composition (body weight, fat mass (FM), FFM) between breast cancer survivors (BCs) and controls. Correlations with body composition were analyzed. We examined if survival year, or being metabolically dysfunctional were predictive variables.
    METHODS: A cross-sectional analysis was conducted on 32 BCs ≤5 years post treatment and 36 healthy controls. Indirect calorimetry measured absolute mREE. Body composition was determined by BOD POD. FFM-adjusted mREE was calculated (mREE/FFM). The Harris-Benedict equation was used to predict REE and determine hyper-/hypometabolism (mREE/pREE). The database of the multidisciplinary breast clinic of the University Hospital of Antwerp was consulted for survival year and metabolic dysfunctions.
    RESULTS: BCs have similar absolute mREE and greater FFM-adjusted mREE compared to controls. Absolute mREE and body composition between BCs differed; adjusted mREE was similar. FFM correlated significantly with absolute mREE in BCs. A significant interaction term was found between survival year and FM for absolute mREE.
    CONCLUSION: BCs have similar absolute mREE, but higher FFM-adjusted mREE. Differences in body composition between BCs are suggested to cause inter-individual variations. We suggest that increased FFM-adjusted mREE is caused by metabolic stress related to cancer/treatment. Accurate measurement of REE and body composition is advised when adapting nutritional strategies, especially in patients at risk for developing metabolic dysfunctions.
    Keywords:  Body composition; Breast cancer; Chemotherapy; Indirect calorimetry; Metabolic dysfunction; Resting energy expenditure
    DOI:  https://doi.org/10.1186/s12905-024-02900-y