Context:
Skeletal muscle from sedentary older adults exhibits reduced mitochondrial abundance and oxidative capacity.
Objective:
The primary objective was to determine whether 8 weeks of combined ...training (CT) has a more robust effect than endurance training (ET) or resistance training (RT) on mitochondrial physiology in healthy young (18–30 years) and older (≥65 years) adults.
Intervention:
Thirty-four young and 31 older adults were randomly assigned to 8 weeks of ET, RT, and control/CT. Control subjects completed 8 weeks of no exercise (control) followed by 8 weeks of CT. Body composition, skeletal muscle strength, and peak oxygen uptake were measured before and after the intervention. Vastus lateralis muscle biopsy samples were obtained before and 48 hours after the intervention. Mitochondrial physiology was evaluated by high-resolution respirometry and expression of mitochondrial proteins and transcription factors by quantitative PCR and immunoblotting.
Results:
ET and CT significantly increased oxidative capacity and expression of mitochondrial proteins and transcription factors. All training modalities improved body composition, cardiorespiratory fitness, and skeletal muscle strength. CT induced the most robust improvements in mitochondria-related outcomes and physical characteristics despite lower training volumes for the ET and RT components. Importantly, most of the adaptations to training occurred independent of age.
Conclusion:
Collectively, these results demonstrate that both ET and CT increase muscle mitochondrial abundance and capacity although CT induced the most robust improvements in the outcomes measured. In conclusion, CT provides a robust exercise regimen to improve muscle mitochondrial outcomes and physical characteristics independent of age.
Serum albumin facilitates the transport of free fatty acids (FFAs) from adipose tissue to other organs. It was not known if impeding this process could protect from hepatic steatosis and metabolic ...dysfunction in obesity. We tested whether albumin knockout (Alb
) mice would exhibit a reduction in plasma FFA concentration, reduced hepatic lipid accumulation, and improved glucoregulation as compared to wild-type (WT) mice. Male homozygous albumin knockout mice (Alb
) and WT controls were fed a low-fat diet (LFD) or high-fat diet (HFD). Alb
mice exhibited a similar body weight gain and body composition as WT on both diets. Despite HFD-induced obesity, Alb
mice were protected from various comorbidities. Compared to WT mice on the HFD, Alb
exhibited lower plasma FFA levels, lower blood glucose levels during glucose tolerance and insulin tolerance tests, and lower hepatic steatosis and inflammation. Alb
mice on HFD also exhibited elevated expression of multiple genes in the liver and adipose tissues, such as peroxisome proliferator-activated receptor α in both tissues, as well as glucose transporter-4 and adiponectin in adipose tissues. The results indicate that albumin's FFA transport function may be involved in the development of hepatic lipid accumulation and dysregulated glucose metabolism in obesity.
Insulin resistance is a global health problem. It has been shown that free fatty acids (FFA) play a major role in insulin resistance. Albumin acts as main fatty acid binding protein in blood. To ...improve understanding of the role of FFA in insulin resistance, we aimed to determine whether lack of serum albumin and the associated suppression of plasma FFA concentration would improve insulin sensitivity in albumin knockout mice compared to wild type mice. Male and female homozygous albumin knockout mice and C57BL/6J wild‐type controls, each fed a chow diet, were studied at 6‐8 weeks of age. Glucose tolerance test, insulin tolerance test, tissue analyses, and plasma proteomics were performed. In both sexes of albumin knockout mice compared to wild‐type mice, we observed lower levels of hepatic diacylglycerol content, as well as lower blood glucose during glucose tolerance test and insulin tolerance test (P < 0.05). The level of mRNA measurement showed higher expression of adiponectin, lipoprotein lipase, diacylglycerol acyltransferase‐1 and ‐2, and glucose transporter‐4 in adipose tissue, as well as lower hepatic perilipin‐2 expression (P<0.05). In agreement with adipose mRNA level analysis, plasma proteomics indicated that circulating adiponectin concentration was higher in albumin knockout compared to wild‐type mice (P<0.05). The results indicate an important role of albumin and plasma FFA concentration in lipid and glucose metabolism. We suggest that the lower plasma FFA concentration in albumin knockout mice compared to wild‐type mice leads to less hepatic diacylglycerol accumulation, and the lower level of this lipotoxic compound may contribute to the enhanced insulin sensitivity.
Abstract
Background
The content of triacylglycerol (TAG) in the liver is known to rapidly increase after a single bout of exercise followed by recovery to sedentary levels. The response of other ...hepatic lipids, and acyl chain composition of lipid classes, would provide a deeper understanding of the response of hepatic lipid metabolism to acute exercise.
Methods
Female mice performed a single bout of continuous exercise (CE), high-intensity interval exercise (HIIE), or no exercise (CON). The total content of various lipids in the liver, and fatty acids within lipid classes, were measured in tissues collected 3 h after exercise (Day 1) and the day following exercise (Day 2).
Results
The total concentration of TAG rose on Day 1 after exercise (
P
< 0.05), with a greater elevation in HIIE than CE (
P
< 0.05), followed by a decline toward CON levels on Day 2. The total concentration of other measured lipid classes was not significantly altered by exercise. However, n-6 polyunsaturated fatty acid relative abundance in diacylglycerol (DAG) was increased by HIIE (
P
< 0.05). In CON liver, TAG content was positively correlated with DAG and phosphatidylethanolamine (
P
< 0.05), while these statistical associations were disrupted in exercised mice on Day 1.
Conclusions
The response of lipid metabolism to exercise involves the coordination of metabolism between various tissues, and the lipid metabolism response to acute exercise places a metabolic burden upon the liver. The present findings describe how the liver copes with this metabolic challenge. The flexibility of the TAG pool size in the liver, and other remodeling of the hepatic lipidome, may be fundamental components of the physiological response to intense exercise.
Acute aerobic exercise increases reactive oxygen species and could potentially damage proteins, but exercise training (ET) enhances mitochondrial respiration irrespective of age. Here, we report a ...differential impact of ET on protein quality in young and older participants. Using mass spectrometry we measured oxidative damage to skeletal muscle proteins before and after 8 weeks of ET and find that young but not older participants reduced oxidative damage to both total skeletal muscle and mitochondrial proteins. Young participants showed higher total and mitochondrial derived semitryptic peptides and 26S proteasome activity indicating increased protein degradation. ET however, increased the activity of the endogenous antioxidants in older participants. ET also increased skeletal muscle content of the mitochondrial deacetylase SIRT3 in both groups. A reduction in the acetylation of isocitrate dehydrogenase 2 was observed following ET that may counteract the effect of acute oxidative stress. In conclusion aging is associated with an inability to improve skeletal muscle and mitochondrial protein quality in response to ET by increasing degradation of damaged proteins. ET does however increase muscle and mitochondrial antioxidant capacity in older individuals, which provides increased buffering from the acute oxidative effects of exercise.
Circulating albumin is expected to play a significant role in the trafficking of plasma free fatty acids (FFA) between tissues, such as FFA transfer from adipose tissue to the liver. However, it was ...not yet known how disrupting FFA binding to albumin in circulation would alter lipid metabolism and any resulting impacts upon control of glycemia. To improve understanding of metabolic control, we aimed to determine whether lack of serum albumin would decrease plasma FFA, hepatic lipid storage, whole body substrate oxidation, and glucose metabolism. Male and female homozygous albumin knockout mice and C57BL/6J wild type controls, each on a standard diet containing a moderate fat content, were studied at 6–8 weeks of age. Indirect calorimetry, glucose tolerance testing, insulin tolerance testing, exercise performance, plasma proteome, and tissue analyses were performed. In both sexes of albumin knockout mice compared to the wild type mice, significant reductions (p < 0.05) were observed for plasma FFA concentration, hepatic triacylglycerol and diacylglycerol content, blood glucose during the glucose tolerance test, and blood glucose during the insulin tolerance test. Albumin deficiency did not reduce whole body fat oxidation over a 24‐h period and did not alter exercise performance in an incremental treadmill test. The system‐level phenotypic changes in lipid and glucose metabolism were accompanied by reduced hepatic perilipin‐2 expression (p < 0.05), as well as increased expression of adiponectin (p < 0.05) and glucose transporter‐4 (p < 0.05) in adipose tissue. The results indicate an important role of albumin and plasma FFA concentration in lipid metabolism and glucoregulation.
Plasma free fatty acids (FFA) bind to albumin in the bloodstream to facilitate their transport from adipose tissue to other sites in the body. Albumin knockout mice exhibited reduced plasma FFA concentration, reduced hepatic lipids (triacylglycerol and diacylglycerol), and improved insulin sensitivity. The results indicate that disrupting the trafficking of FFA between tissues, through disruption of albumin expression, may lead to altered lipid metabolism and maintenance of lower blood glucose concentration.
Menopause is associated with fatty liver, glucose dysregulation, increased body fat, and impaired bone quality. Previously, it was demonstrated that single sessions of high-intensity interval ...exercise (HIIE) are more effective than distance- and duration-matched continuous exercise (CE) on altering hepatic triglyceride (TG) metabolism and very-low density lipoprotein-TG (VLDL-TG) secretion.
Six weeks training using these modalities was examined for effects on hepatic TG metabolism/secretion, glucose tolerance, body composition, and bone mineral density (BMD) in ovariectomized (OVX) and sham-operated (SHAM) mice. OVX and SHAM were assigned to distance- and duration-matched CE and HIIE, or sedentary control.
Energy expenditure during exercise was confirmed to be identical between CE and HIIE and both similarly reduced post-exercise absolute carbohydrate oxidation and spontaneous physical activity (SPA). OVX vs. SHAM displayed impaired glucose tolerance and greater body fat despite lower hepatic TG, and these outcomes were not affected by training. Only HIIE increased hepatic AMPK in OVX and SHAM, but neither training type impacted VLDL-TG secretion. As expected, BMD was lower in OVX, and training did not affect long bones.
The results reveal intensity-dependent effects on hepatic AMPK expression and general exercise effects on subsequent SPA and substrate oxidation that is independent of estrogen status. These findings support the notion that HIIE can impact aspects of liver physiology in females while the effects of exercise on whole body substrate selection appear to be independent of training intensity. However, neither exercise approach mitigated the impairment in glucose tolerance and elevated body fat occurring in OVX mice.
•CE and HIIE reduced post-exercise absolute carbohydrate oxidation and spontaneous physical activity.•OVX animals displayed impaired glucose tolerance and greater body fat despite lower hepatic TG.•Only HIIE increased hepatic AMPK in OVX and SHAM, but neither training type impacted VLDL-TG secretion.•BMD was lower in OVX, and training did not affect long bones.•HIIE can impact aspects of liver physiology and whole body substrate selection in females.
Liver fatty acid-binding protein (LFABP) binds long-chain fatty acids with high affinity and is abundantly expressed in the liver and small intestine. Although LFABP is thought to function in ...intracellular lipid trafficking, studies of LFABP-null (LFABP−/−) mice have also indicated a role in regulating systemic energy homeostasis. We and others have reported that LFABP−/− mice become more obese than wildtype (WT) mice upon high-fat feeding. Here, we show that despite increased body weight and fat mass, LFABP−/− mice are protected from a high-fat feeding–induced decline in exercise capacity, displaying an approximate doubling of running distance compared with WT mice. To understand this surprising exercise phenotype, we focused on metabolic alterations in the skeletal muscle due to LFABP ablation. Compared with WT mice, resting skeletal muscle of LFABP−/− mice had higher glycogen and intramuscular triglyceride levels as well as an increased fatty acid oxidation rate and greater mitochondrial enzyme activities, suggesting higher substrate availability and substrate utilization capacity. Dynamic changes in the respiratory exchange ratio during exercise indicated that LFABP−/− mice use more carbohydrate in the beginning of an exercise period and then switch to using lipids preferentially in the later stage. Consistently, LFABP−/− mice exhibited a greater decrease in muscle glycogen stores during exercise and elevated circulating free fatty acid levels postexercise. We conclude that, because LFABP is not expressed in muscle, its ablation appears to promote interorgan signaling that alters muscle substrate levels and metabolism, thereby contributing to the prevention of high-fat feeding–induced skeletal muscle impairment.
Spinal cord injury (SCI) results in disordered fat metabolism. Autonomic decentralization might contribute to dyslipidemia in SCI, in part by influencing the uptake of dietary fats through the ...gut-lymph complex. However, the neurogenic contributions to dietary fat metabolism are unknown in this population. We present a subset of results from an ongoing registered clinical trial (NCT03691532) related to dietary fat absorption. We fed a standardized (20 kcal⋅kgFFM
) liquid meal tolerance test (50% carb, 35% fat, and 15% protein) that contained stable isotope lipid tracer (5 mg⋅kgFFM
U-
Cpalmitate) to persons with and without motor complete thoracic SCI. Blood samples were collected at six postprandial time points over 400 min. Changes in dietary fatty acid incorporated into the triacylglycerol (TAG) pool ("exogenous TAG") were used as a marker of dietary fat absorption. This biomarker showed that those with paraplegia had a lower amplitude than non-injured participants at Post
(52.4 ± 11.0 vs. 77.5 ± 16.0 μM), although this failed to reach statistical significance (
= 0.328). However, group differences in the time course of absorption were notable. The injury level was also strongly correlated with time-to-peak exogenous TAG concentration (
= -0.806,
= 0.012), with higher injuries resulting in a slower rise in exogenous TAG. This time course documenting exogenous TAG change is the first to show a potential neurogenic alteration in SCI dietary fat absorption.
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