Motor unit firing rates increase in prepubescent youth following linear periodization resistance exercise training.

PURPOSE: The purpose was to examine the effects of 8-weeks (3 days/week) of linear periodization resistance exercise training (RET) on neuromuscular function in prepubescent youth. METHODS: Twenty-five healthy prepubescent youth (11 males, 14 females, age = 9.1 ± 0.8 years) completed the RET (n = 17) or served as controls (CON, n = 8). Isometric maximal voluntary contractions (MVCs) and trapezoidal submaximal contractions at 35 and 60% MVC of the right leg extensors were performed with surface electromyography (EMG) recorded from the leg extensors [vastus lateralis (VL), rectus femoris, and vastus medialis] and flexors (biceps femoris and semitendinosus). EMG amplitude of the leg extensors and flexors were calculated during the MVCs. Motor unit (MU) action potential trains were decomposed from the surface EMG of the VL for the 35 and 60% MVCs. MU firing rates and action potential amplitudes were regressed against recruitment threshold with the y-intercepts and slopes calculated for each contraction. Total leg extensor muscle cross-sectional area (CSA) was collected using ultrasound images. ANOVA models were used to examine potential differences. RESULTS: Isometric strength increased post-RET (P = 0.006) with no changes in leg extensor and flexor EMG amplitude. Furthermore, there were no changes in total CSA or the MU action potential amplitude vs. recruitment threshold relationships. However, there were increases in the firing rates of the higher-threshold MUs post-RET as indicated with greater y-intercepts (P = 0.003) from the 60% MVC and less negative slope (P = 0.004) of the firing rates vs. recruitment threshold relationships at 35% MVC. CONCLUSIONS: MU adaptations contribute to strength increases following RET in prepubescent youth.

Hepatic malonyl-CoA synthesis restrains gluconeogenesis by suppressing fat oxidation, pyruvate carboxylation, and amino acid availability.

Acetyl-CoA carboxylase (ACC) promotes prandial liver metabolism by producing malonyl-CoA, a substrate for de novo lipogenesis and an inhibitor of CPT-1-mediated fat oxidation. We report that inhibition of ACC also produces unexpected secondary effects on metabolism. Liver-specific double ACC1/2 knockout (LDKO) or pharmacologic inhibition of ACC increased anaplerosis, tricarboxylic acid (TCA) cycle intermediates, and gluconeogenesis by activating hepatic CPT-1 and pyruvate carboxylase flux in the fed state. Fasting should have marginalized the role of ACC, but LDKO mice maintained elevated TCA cycle intermediates and preserved glycemia during fasting. These effects were accompanied by a compensatory induction of proteolysis and increased amino acid supply for gluconeogenesis, which was offset by increased protein synthesis during feeding. Such adaptations may be related to Nrf2 activity, which was induced by ACC inhibition and correlated with fasting amino acids. The findings reveal unexpected roles for malonyl-CoA synthesis in liver and provide insight into the broader effects of pharmacologic ACC inhibition.

VCD-induced menopause mouse model reveals reprogramming of hepatic metabolism.

OBJECTIVE: Menopause adversely impacts systemic energy metabolism and increases the risk of metabolic disease(s) including hepatic steatosis, but the mechanisms are largely unknown. Dosing female mice with vinyl cyclohexene dioxide (VCD) selectively causes follicular atresia in ovaries, leading to a murine menopause-like phenotype. METHODS: In this study, we treated female C57BL6/J mice with VCD (160 mg/kg i.p. for 20 consecutive days followed by verification of the lack of estrous cycling) to investigate changes in body composition, energy expenditure (EE), hepatic mitochondrial function, and hepatic steatosis across different dietary conditions. RESULTS: VCD treatment induced ovarian follicular loss and increased follicle-stimulating hormone (FSH) levels in female mice, mimicking a menopause-like phenotype. VCD treatment did not affect body composition, or EE in mice on a low-fat diet (LFD) or in response to a short-term (1-week) high-fat, high sucrose diet (HFHS). However, the transition to a HFHS lowered cage activity in VCD mice. A chronic HFHS diet (16 weeks) significantly increased weight gain, fat mass, and hepatic steatosis in VCD-treated mice compared to HFHS-fed controls. In the liver, VCD mice showed suppressed hepatic mitochondrial respiration on LFD, while chronic HFHS resulted in compensatory increases in hepatic mitochondrial respiration. Also, liver RNA sequencing revealed that VCD promoted global upregulation of hepatic lipid/cholesterol synthesis pathways. CONCLUSION: Our findings suggest that the VCD-induced menopause model compromises hepatic mitochondrial function and lipid/cholesterol homeostasis that sets the stage for HFHS diet-induced steatosis while also increasing susceptibility to obesity.

Disruption of hepatic mitochondrial pyruvate and amino acid metabolism impairs gluconeogenesis and endurance exercise capacity in mice.

Exercise robustly increases the glucose demands of skeletal muscle. This demand is met by not only muscle glycogenolysis but also 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 hepatic gluconeogenic efficiency and capacity on exercise performance by deleting mitochondrial pyruvate carrier 2 (MPC2) and/or alanine transaminase 2 (ALT2) in the liver of mice. We found that deletion of MPC2 or ALT2 alone did not significantly affect time to exhaustion or postexercise glucose concentrations in treadmill exercise tests, but mice lacking both MPC2 and ALT2 in hepatocytes (double knockout, 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. 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 cross talk during exercise as described by the Cahill and Cori cycles.NEW & NOTEWORTHY Martino and colleagues examined the effects of inhibiting hepatic gluconeogenesis on exercise performance and systemic metabolism during treadmill exercise in mice. Combined inhibition of gluconeogenesis from lactate/pyruvate and alanine impaired exercise endurance and led to hypoglycemia during and after exercise. In contrast, suppressing either pyruvate-mediated or alanine-mediated gluconeogenesis alone had no effect on these parameters. These findings provide new insight into the molecular nodes that coordinate the metabolic responses of muscle and liver during exercise.

High-dose atorvastatin therapy progressively decreases skeletal muscle mitochondrial respiratory capacity in humans.

BACKGROUNDWhile the benefits of statin therapy on atherosclerotic cardiovascular disease are clear, patients often experience mild to moderate skeletal myopathic symptoms, the mechanism for which is unknown. This study investigated the potential effect of high-dose atorvastatin therapy on skeletal muscle mitochondrial function and whole-body aerobic capacity in humans.METHODSEight overweight (BMI, 31.9 ± 2.0) but otherwise healthy sedentary adults (4 females, 4 males) were studied before (day 0) and 14, 28, and 56 days after initiating atorvastatin (80 mg/d) therapy.RESULTSMaximal ADP-stimulated respiration, measured in permeabilized fiber bundles from muscle biopsies taken at each time point, declined gradually over the course of atorvastatin treatment, resulting in > 30% loss of skeletal muscle mitochondrial oxidative phosphorylation capacity by day 56. Indices of in vivo muscle oxidative capacity (via near-infrared spectroscopy) decreased by 23% to 45%. In whole muscle homogenates from day 0 biopsies, atorvastatin inhibited complex III activity at midmicromolar concentrations, whereas complex IV activity was inhibited at low nanomolar concentrations.CONCLUSIONThese findings demonstrate that high-dose atorvastatin treatment elicits a striking progressive decline in skeletal muscle mitochondrial respiratory capacity, highlighting the need for longer-term dose-response studies in different patient populations to thoroughly define the effect of statin therapy on skeletal muscle health.FUNDINGNIH R01 AR071263.

Divergence in aerobic capacity and energy expenditure influence metabolic tissue mitochondrial protein synthesis rates in aged rats.

Age-associated declines in aerobic capacity promote the development of various metabolic diseases. In rats selectively bred for high/low intrinsic aerobic capacity, greater aerobic capacity reduces susceptibility to metabolic disease while increasing longevity. However, little remains known how intrinsic aerobic capacity protects against metabolic disease, particularly with aging. Here, we tested the effects of aging and intrinsic aerobic capacity on systemic energy expenditure, metabolic flexibility and mitochondrial protein synthesis rates using 24-month-old low-capacity (LCR) or high-capacity runner (HCR) rats. Rats were fed low-fat diet (LFD) or high-fat diet (HFD) for eight weeks, with energy expenditure (EE) and metabolic flexibility assessed utilizing indirect calorimetry during a 48 h fast/re-feeding metabolic challenge. Deuterium oxide (D2O) labeling was used to assess mitochondrial protein fraction synthesis rates (FSR) over a 7-day period. HCR rats possessed greater EE during the metabolic challenge. Interestingly, HFD induced changes in respiratory exchange ratio (RER) in male and female rats, while HCR female rat RER was largely unaffected by diet. In addition, analysis of protein FSR in skeletal muscle, brain, and liver mitochondria showed tissue-specific adaptations between HCR and LCR rats. While brain and liver protein FSR were altered by aerobic capacity and diet, these effects were less apparent in skeletal muscle. Overall, we provide evidence that greater aerobic capacity promotes elevated EE in an aged state, while also regulating metabolic flexibility in a sex-dependent manner. Modulation of mitochondrial protein FSR by aerobic capacity is tissue-specific with aging, likely due to differential energetic requirements by each tissue.

Exposure to early-life stress impairs weight-loss maintenance success in mice.

OBJECTIVE: The impact of early-life stress on weight-loss maintenance is unknown. METHODS: Mice underwent neonatal maternal separation (NMS) from 0 to 3 weeks and were weaned onto a high-fat sucrose diet (HFSD) from 3 to 20 weeks. Calorie-restricted weight loss on a low-fat sucrose diet (LFSD) occurred over 2 weeks to induce a 20% loss in body weight, which was maintained for 6 weeks. After weight loss, half of the mice received running wheels, and the other half remained sedentary. Mice were then fed ad libitum on an HFSD or LFSD for 10 weeks and were allowed to regain body weight. RESULTS: NMS mice had greater weight regain, total body weight, and adiposity compared with naïve mice. During the first week of refeeding, NMS mice had increased food intake and were in a greater positive energy balance than naïve mice. Female mice were more susceptible to NMS-induced effects, including increases in adiposity. NMS and naïve females were more susceptible to HFSD-induced weight regain. Exercise was beneficial in the first week of regain in male mice, but, long-term, only those on the LFSD benefited from exercise. As expected, HFSD led to greater weight regain than LFSD. CONCLUSIONS: Early-life stress increases weight regain in mice.

Divergence in aerobic capacity influences hepatic and systemic metabolic adaptations to bile acid sequestrant and short-term high-fat/sucrose feeding in rats.

High versus low aerobic capacity significantly impacts the risk for metabolic diseases. Rats selectively bred for high or low intrinsic aerobic capacity differently modify hepatic bile acid metabolism in response to high-fat diets (HFDs). Here we tested if a bile acid sequestrant would alter hepatic and whole body metabolism differently in rats with high and low aerobic capacity fed a 1-wk HFD. Male rats (8 mo of age) that were artificially selected to be high (HCR) and low-capacity runners (LCR) with divergent intrinsic aerobic capacities were transitioned from a low-fat diet (LFD, 10% fat) to an HFD (45% fat) with or without a bile acid sequestrant (BA-Seq, 2% cholestyramine resin) for 7 days while maintained in an indirect calorimetry system. HFD + BA-Seq increased fecal excretion of lipids and bile acids and prevented weight and fat mass gain in both strains. Interestingly, HCR rats had increased adaptability to enhance fecal bile acid and lipid loss, resulting in more significant energy loss than their LCR counterpart. In addition, BA-Seq induced a greater expression of hepatic CYP7A1 gene expression, the rate-limiting enzyme of bile acid synthesis in HCR rats both on HFD and HFD + BA-Seq diets. HCR displayed a more significant reduction of RQ in response to HFD than LCR, but HFD + BA-Seq lowered RQ in both groups compared with HFD alone, demonstrating a pronounced impact on metabolic flexibility. In conclusion, BA-Seq provides uniform metabolic benefits for metabolic flexibility and adiposity, but rats with higher aerobic capacity display adaptability for hepatic bile acid metabolism.NEW & NOTEWORTHY The administration of bile acid sequestrant (BA-Seq) has uniform metabolic benefits in terms of metabolic flexibility and adiposity in rats with high and low aerobic capacity. However, rats with higher aerobic capacity demonstrate greater adaptability in hepatic bile acid metabolism, resulting in increased fecal bile acid and lipid loss, as well as enhanced fecal energy loss.

Disruption of Hepatic Mitochondrial Pyruvate and Amino Acid Metabolism Impairs Gluconeogenesis and Endurance Exercise Capacity in Mice.

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.

Exposure to early life stress impairs weight loss maintenance success in mice.

Early life stress increases obesity risk, but its impact on weight loss maintenance is unknown. Mice underwent neonatal maternal separation (NMS) from 0-3 weeks and were weaned onto high fat sucrose diet (HFSD) from 3-20 weeks. Calorie-restricted weight loss on a low fat sucrose diet (LFSD) occurred over 2 weeks to induce a 20% loss in body weight, which was maintained for 6 weeks. After weight loss, half the mice received running wheels (EX) the other half remained sedentary (SED). Mice were then fed ad libitum on HFSD or LFSD for 10 weeks and allowed to regain body weight. NMS mice had greater weight regain, total body weight and adiposity compared to naïve mice. During the first week of refeeding, NMS mice had increased food intake and were in a greater positive energy balance than naïve mice, but total energy expenditure was not affected by NMS. Female mice were more susceptible to NMS-induced effects, including increases in adiposity. NMS and naïve females were more susceptible to HFSD-induce weight regain. Exercise was beneficial in the first week of regain in male mice, but long-term only those on LFSD benefited from EX. As expected, HFSD led to greater weight regain than LFSD.

Early-life stress perturbs the epigenetics of Cd36 concurrent with adult onset of NAFLD in mice.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in the U.S. and worldwide. The roles of early postnatal life stress (EPLS) and the fatty acid translocase (CD36) on the pathogenesis of adult-onset NAFLD remain unknown. We hypothesized that EPLS, in the form of neonatal maternal separation (NMS), would predispose mice towards developing adult NAFLD, increase hepatic CD36 expression, and differentially methylate Cd36 promoter concurrently. METHODS: NMS was performed on mice from postnatal day 1 to 21 and a high-fat/high-sucrose (HFS) diet was started at 4 weeks of age to generate four experimental groups: Naive-control diet (CD), Naive-HFS, NMS-CD, and NMS-HFS. RESULTS: NMS alone caused NAFLD in adult male mice at 25 weeks of age. The effects of NMS and HFS were generally additive in terms of NAFLD, hepatic Cd36 mRNA levels, and hepatic Cd36 promoter DNA hypomethylation. Cd36 promoter methylation negatively correlated with Cd36 mRNA levels. Two differentially methylated regions (DMRs) within Cd36 promoter regions appeared to be vulnerable to NMS in the mouse. CONCLUSIONS: Our findings suggest that NMS increases the risk of an individual, particularly male, towards NAFLD when faced with a HFS diet later in life. IMPACT: The key message of this article is that neonatal maternal separation and a postweaning high-fat/high-sucrose diet increased the risk of an individual, particularly male, towards NAFLD in adult life. What this study adds to the existing literature includes the identification of two vulnerable differentially methylated regions in hepatic Cd36 promoters whose methylation levels very strongly negatively correlated with Cd36 mRNA. The impact of this article is that it provides an early-life environment-responsive gene/promoter methylation model and an animal model for furthering the mechanistic study on how the insults in early-life environment are "transmitted" into adulthood and caused NAFLD.

Pre- and Post-Sexual Maturity Liver-specific ERα Knockout Does Not Impact Hepatic Mitochondrial Function.

Compared with males, premenopausal women and female rodents are protected against hepatic steatosis and present with higher functioning mitochondria (greater hepatic mitochondrial respiration and reduced H2O2 emission). Despite evidence that estrogen action mediates female protection against steatosis, mechanisms remain unknown. Here we validated a mouse model with inducible reduction of liver estrogen receptor alpha (ERα) (LERKO) via adeno-associated virus (AAV) Cre. We phenotyped the liver health and mitochondrial function of LERKO mice (n = 10-12 per group) on a short-term high-fat diet (HFD), and then tested whether timing of LERKO induction at 2 timepoints (sexually immature: 4 weeks old [n = 11 per group] vs sexually mature: 8-10 weeks old [n = 8 per group]) would impact HFD-induced outcomes. We opted for an inducible LERKO model due to known estrogen-mediated developmental programming, and we reported both receptor and tissue specificity with our model. Control mice were ERαfl/fl receiving AAV with green fluorescent protein (GFP) only. Results show that there were no differences in body weight/composition or hepatic steatosis in LERKO mice with either short-term (4-week) or chronic (8-week) high-fat feeding. Similarly, LERKO genotype nor timing of LERKO induction (pre vs post sexual maturity) did not alter hepatic mitochondrial O2 and H2O2 flux, coupling, or OXPHOS protein. Transcriptomic analysis showed that hepatic gene expression in LERKO was significantly influenced by developmental stage. Together, these studies suggest that hepatic ERα is not required in female protection against HFD-induced hepatic steatosis nor does it mediate sexual dimorphism in liver mitochondria function.

Ketolysis is required for the proper development and function of the somatosensory nervous system.

Ketogenic diets are emerging as protective interventions in preclinical and clinical models of somatosensory nervous system disorders. Additionally, dysregulation of succinyl-CoA 3-oxoacid CoA-transferase 1 (SCOT, encoded by Oxct1), the fate-committing enzyme in mitochondrial ketolysis, has recently been described in Friedreich's ataxia and amyotrophic lateral sclerosis. However, the contribution of ketone metabolism in the normal development and function of the somatosensory nervous system remains poorly characterized. We generated sensory neuron-specific, Advillin-Cre knockout of SCOT (Adv-KO-SCOT) mice and characterized the structure and function of their somatosensory system. We used histological techniques to assess sensory neuronal populations, myelination, and skin and spinal dorsal horn innervation. We also examined cutaneous and proprioceptive sensory behaviors with the von Frey test, radiant heat assay, rotarod, and grid-walk tests. Adv-KO-SCOT mice exhibited myelination deficits, altered morphology of putative Aδ soma from the dorsal root ganglion, reduced cutaneous innervation, and abnormal innervation of the spinal dorsal horn compared to wildtype mice. Synapsin 1-Cre-driven knockout of Oxct1 confirmed deficits in epidermal innervation following a loss of ketone oxidation. Loss of peripheral axonal ketolysis was further associated with proprioceptive deficits, yet Adv-KO-SCOT mice did not exhibit drastically altered cutaneous mechanical and thermal thresholds. Knockout of Oxct1 in peripheral sensory neurons resulted in histological abnormalities and severe proprioceptive deficits in mice. We conclude that ketone metabolism is essential for the development of the somatosensory nervous system. These findings also suggest that decreased ketone oxidation in the somatosensory nervous system may explain the neurological symptoms of Friedreich's ataxia.

Exercise drives metabolic integration between muscle, adipose and liver metabolism and protects against aging-related diseases.

Over the last few decades, metabolic disease rates have been on the rise, and this is partially due to older individuals (>65 years of age) making up a higher percentage of the general population. As a result, older age is recognized as a major factor in the global metabolic disorders epidemic (insulin resistance, type 2 diabetes (T2D), fatty liver) and chronic disease conditions (Alzheimer's, cardiovascular disease, etc.). In addition, aging synergizes with obesity and chronic physical inactivity to further drive risk. Exercise or moderate to vigorous physical activity induces adaptations that positively modulate metabolic health in all age groups, including older individuals. Most studies have focused on how aging negatively impacts metabolic function in a specific tissue and how exercise offsets those declines and improves metabolic function. However, during exercise, multiple tissues work in concert to coordinate energy metabolism and maintain metabolic homeostasis. As a result, the metabolic stress of exercise results in long-term adaptations, which are associated with protection against metabolic disease states through mechanisms that are incompletely understood and even less investigated in older individuals (>65 years of age). This review focuses on how exercise affects skeletal muscle, liver, and adipose metabolism in an integrated fashion to modulate improved metabolic health in the context of aging.

Exercise and inactivity as modifiers of ß cell function and type 2 diabetes risk.

Exercise and regular physical activity are beneficial for the prevention and management of metabolic diseases such as obesity and type 2 diabetes, whereas exercise cessation, defined as deconditioning from regular exercise or physical activity that has lasted for a period of months to years, can lead to metabolic derangements that drive disease. Adaptations to the insulin-secreting pancreatic ß-cells are an important benefit of exercise, whereas less is known about how exercise cessation affects these cells. Our aim is to review the impact that exercise and exercise cessation have on ß-cell function, with a focus on the evidence from studies examining glucose-stimulated insulin secretion (GSIS) using gold-standard techniques. Potential mechanisms by which the ß-cell adapts to exercise, including exerkine and incretin signaling, autonomic nervous system signaling, and changes in insulin clearance, will also be explored. We will highlight areas for future research.

Relationship of Muscle Apolipoprotein E Expression with Markers of Cellular Stress, Metabolism, and Blood Biomarkers in Cognitively Healthy and Impaired Older Adults.

BACKGROUND: Individuals with mild cognitive impairment (MCI) have reduced lipid-stimulated mitochondrial respiration in skeletal muscle. A major risk factor for Alzheimer's disease (AD), the apolipoprotein E4 (APOE4) allele, is implicated in lipid metabolism and is associated with metabolic and oxidative stress that can result from dysfunctional mitochondria. Heat shock protein 72 (Hsp72) is protective against these stressors and is elevated in the AD brain. OBJECTIVE: Our goal was to characterize skeletal muscle ApoE and Hsp72 protein expression in APOE4 carriers in relationship to cognitive status, muscle mitochondrial respiration and AD biomarkers. METHODS: We analyzed previously collected skeletal muscle tissue from 24 APOE4 carriers (60y+) who were cognitively healthy (CH, n = 9) or MCI (n = 15). We measured ApoE and Hsp72 protein levels in muscle and phosphorylated tau181 (pTau181) levels in plasma, and leveraged previously collected data on APOE genotype, mitochondrial respiration during lipid oxidation, and VO2 max. RESULTS: Muscle ApoE (p = 0.013) and plasma pTau181 levels (p < 0.001) were higher in MCI APOE4 carriers. Muscle ApoE positively correlated with plasma pTau181 in all APOE4 carriers (R2 = 0.338, p = 0.003). Hsp72 expression negatively correlated with ADP (R2 = 0.775, p = <0.001) and succinate-stimulated respiration (R2 = 0.405, p = 0.003) in skeletal muscle of MCI APOE4 carriers. Plasma pTau181 negatively tracked with VO2 max in all APOE4 carriers (R2 = 0.389, p = 0.003). Analyses were controlled for age. CONCLUSION: This work supports a relationship between cellular stress in skeletal muscle and cognitive status in APOE4 carriers.

High-fat/high-sucrose diet worsens metabolic outcomes and widespread hypersensitivity following early-life stress exposure in female mice.

Exposure to stress early in life has been associated with adult-onset comorbidities such as chronic pain, metabolic dysregulation, obesity, and inactivity. We have established an early-life stress model using neonatal maternal separation (NMS) in mice, which displays evidence of increased body weight and adiposity, widespread mechanical allodynia, and hypothalamic-pituitary-adrenal axis dysregulation in male mice. Early-life stress and consumption of a Western-style diet contribute to the development of obesity; however, relatively few preclinical studies have been performed in female rodents, which are known to be protected against diet-induced obesity and metabolic dysfunction. In this study, we gave naïve and NMS female mice access to a high-fat/high-sucrose (HFS) diet beginning at 4 wk of age. Robust increases in body weight and fat were observed in HFS-fed NMS mice during the first 10 wk on the diet, driven partly by increased food intake. Female NMS mice on an HFS diet showed widespread mechanical hypersensitivity compared with either naïve mice on an HFS diet or NMS mice on a control diet. HFS diet-fed NMS mice also had impaired glucose tolerance and fasting hyperinsulinemia. Strikingly, female NMS mice on an HFS diet showed evidence of hepatic steatosis with increased triglyceride levels and altered glucocorticoid receptor levels and phosphorylation state. They also exhibited increased energy expenditure as observed via indirect calorimetry and expression of proinflammatory markers in perigonadal adipose. Altogether, our data suggest that early-life stress exposure increased the susceptibility of female mice to develop diet-induced metabolic dysfunction and pain-like behaviors.

Sexually dimorphic hepatic mitochondrial adaptations to exercise: a mini-review.

Exercise is a physiological stress that disrupts tissue and cellular homeostasis while enhancing systemic metabolic energy demand mainly through the increased workload of skeletal muscle. Although the extensive focus has been on skeletal muscle adaptations to exercise, the liver senses these disruptions in metabolic energy homeostasis and responds to provide the required substrates to sustain increased demand. Hepatic metabolic flexibility is an energetically costly process that requires continuous mitochondrial production of the cellular currency ATP. To do so, the liver must maintain a healthy functioning mitochondrial pool, attained through well-regulated and dynamic processes. Intriguingly, some of these responses are sex-dependent. This mini-review examines the hepatic mitochondrial adaptations to exercise with a focus on sexual dimorphism.

Ketolysis is Required for the Proper Development and Function of the Somatosensory Nervous System.

Ketogenic diets are emerging as protective interventions in preclinical and clinical models of somatosensory nervous system disorders. Additionally, dysregulation of succinyl-CoA 3-oxoacid CoA-transferase 1 (SCOT, encoded by Oxct1 ), the fate-committing enzyme in mitochondrial ketolysis, has recently been described in Friedreich's ataxia and amyotrophic lateral sclerosis. However, the contribution of ketone metabolism in the normal development and function of the somatosensory nervous system remains poorly characterized. We generated sensory neuron-specific, Advillin-Cre knockout of SCOT (Adv-KO-SCOT) mice and characterized the structure and function of their somatosensory system. We used histological techniques to assess sensory neuronal populations, myelination, and skin and spinal dorsal horn innervation. We also examined cutaneous and proprioceptive sensory behaviors with the von Frey test, radiant heat assay, rotarod, and grid-walk tests. Adv-KO-SCOT mice exhibited myelination deficits, altered morphology of putative Aδ soma from the dorsal root ganglion, reduced cutaneous innervation, and abnormal innervation of the spinal dorsal horn compared to wildtype mice. Synapsin 1-Cre-driven knockout of Oxct1 confirmed deficits in epidermal innervation following a loss of ketone oxidation. Loss of peripheral axonal ketolysis was further associated with proprioceptive deficits, yet Adv-KO-SCOT mice did not exhibit drastically altered cutaneous mechanical and thermal thresholds. Knockout of Oxct1 in peripheral sensory neurons resulted in histological abnormalities and severe proprioceptive deficits in mice. We conclude that ketone metabolism is essential for the development of the somatosensory nervous system. These findings also suggest that decreased ketone oxidation in the somatosensory nervous system may explain the neurological symptoms of Friedreich's ataxia.