Sex differences in mitochondrial respiratory function in human skeletal muscle.

Mitochondrial bioenergetic contributions to sex differences in human skeletal muscle metabolism remain poorly defined. The primary aim of this study was to determine whether mitochondrial respiratory kinetics differed between healthy young men and women in permeabilized skeletal muscle fibers. While men and women displayed similar ( P > 0.05) maximal respiration rates and abundance of mitochondrial/adenosine diphosphate (ADP) transport proteins, women had lower ( P < 0.05) mitochondrial ADP sensitivity (+30% apparent Km) and absolute respiration rates at a physiologically relevant ADP concentration (100 µM). Moreover, although men and women exhibited similar carnitine palmitoyl transferase-I protein content- and palmitoyl-CoA-supported respiration, women displayed greater sensitivity to malonyl-CoA-mediated respiratory inhibition. These data establish baseline sex differences in mitochondrial bioenergetics and provide the foundation for studying mitochondrial function within the context of metabolic perturbations and diseases that affect men and women differently.

Microvascular adaptations to resistance training are independent of load in resistance-trained young men.

Resistance training promotes microvasculature expansion; however, it remains unknown how different resistance training programs contribute to angiogenesis. Thus, we recruited experienced resistance-trained participants and determined the effect of 12 wk of either high-repetition/low-load or low-repetition/high-load resistance training performed to volitional fatigue on muscle microvasculature. Twenty men performed either a high-repetition [20-25 repetitions, 30-50% of 1-repetition maximum (1RM); n = 10] or a low-repetition (8-12 repetitions, 75-90% of 1RM; n = 10) resistance training program. Muscle biopsies were taken before and after resistance training, and immunohistochemistry was used to assess fiber type (I and II)-specific microvascular variables. High-repetition/low-load and low-repetition/high-load groups were not different in any variable before resistance training. Both protocols resulted in an increase in capillarization. Specifically, after resistance training, the capillary-to-fiber ratio, capillary contacts, and capillary-to-fiber perimeter exchange index were elevated, and sharing factor was reduced. These data demonstrate that resistance training performed to volitional failure, using either high repetition/low load or low repetition/high load, induced similar microvascular adaptations in recreationally resistance-trained young men.

α-Linolenic acid and exercise training independently, and additively, decrease blood pressure and prevent diastolic dysfunction in obese Zucker rats.

KEY POINTS: α-linolenic acid (ALA) and exercise training both attenuate hyperlipidaemia-related cardiovascular derangements, however, there is a paucity of information pertaining to their mechanisms of action when combined. We investigated both the independent and combined effects of exercise training and ALA consumption in obese Zucker rats, aiming to determine the potential for additive improvements in cardiovascular function. ALA and exercise training independently improved cardiac output, end-diastolic volume, left ventricular fibrosis and mean blood pressure following a 4 week intervention. Combining ALA and endurance exercise yielded greater improvements in these parameters, independent of changes in markers of oxidative stress or endogenous anti-oxidants. We postulate that divergent mechanisms of action may explain these changes: ALA increases peripheral vasodilation, and exercise training stimulates angiogenesis. ABSTRACT: Although α-linolenic acid (ALA) and endurance exercise training independently attenuate hyperlipidaemia-related cardiovascular derangements, there is a paucity of information pertaining to their mechanisms of action and efficacy when combined as a preventative therapeutic approach. Therefore, we used obese Zucker rats to investigate the independent and combined effects of these interventions on cardiovascular disease. Specifically, animals were randomly assigned to one of the following groups: control diet-sedentary, ALA supplemented-sedentary, control diet-exercise trained or ALA supplemented-exercise trained. Following a 4 week intervention, although the independent and combined effects of ALA and exercise reduced (P < 0.05) the serum free/esterified cholesterol ratio, only the ALA supplemented-exercise trained animals displayed a reduction in the content of both serum free and esterified cholesterol. Moreover, although ALA and endurance training individually increased cardiac output, stroke volume and end-diastolic volume, as well as reduced left ventricle fibrosis, mean blood pressure and total peripheral resistance, these responses were all greater following the combined intervention (ALA supplemented-exercise trained). These effects occurred independent of changes in oxidative phosphorylation proteins, markers of oxidative stress or endogenous anti-oxidant capacity. We propose that the beneficial effects of a combined intervention occur as a result of divergent mechanisms of action elicited by ALA and endurance exercise because only exercise training increased the capillary content in the left ventricle and skeletal muscle, and tended to decrease protein carbonylation in the left ventricle (P = 0.06). Taken together, our data indicate that combining ALA and endurance exercise provides additional improvements in cardiovascular disease risk reduction compared to singular interventions in the obese Zucker rat.

High-intensity interval and endurance training are associated with divergent skeletal muscle adaptations in a rodent model of hypertension.

Skeletal muscle is extremely adaptable to a variety of metabolic challenges, as both traditional moderate-intensity endurance (ET) and high-intensity interval training (HIIT) increases oxidative potential in a coordinated manner. Although these responses have been clearly demonstrated in healthy individuals, it remains to be determined whether both produce similar responses in the context of hypertension, one of the most prevalent and costly diseases worldwide. Therefore, in the current study, we used the Dahl sodium-sensitive rat, a model of hypertension, to determine the molecular responses to 4 wk of either ET or HIIT in the red (RG) and white gastrocnemius (WG) muscles. In the RG, both ET and HIIT increased the content of electron transport chain proteins and increased succinate dehydrogenase (SDH) content in type I fibers. Although both intensities of exercise shifted fiber type in RG (increased IIA, decreased IIX), only HIIT was associated with a reduction in endothelial nitric oxide synthase and an increase in HIF-1α proteins. In the WG, both ET and HIIT increased markers of the electron transport chain; however, HIIT decreased SDH content in a fiber-specific manner. ET increased type IIA, decreased IIB fibers, and increased capillarization, while, in contrast, HIIT increased the percentage of IIB fibers, decreased capillary-to-fiber ratios, decreased endothelial nitric oxide synthase, and increased hypoxia inducible factor-1α (HIF-1α) protein. Altogether, these data show that unlike in healthy animals, ET and HIIT have divergent effects in the skeletal muscle of hypertensive rats. This suggests ET may be optimal at improving the oxidative capacity of skeletal muscle in animals with hypertension.

Potato Protein Isolate Stimulates Muscle Protein Synthesis at Rest and with Resistance Exercise in Young Women.

Skeletal muscle myofibrillar protein synthesis (MPS) increases in response to protein feeding and to resistance exercise (RE), where each stimuli acts synergistically when combined. The efficacy of plant proteins such as potato protein (PP) isolate to stimulate MPS is unknown. We aimed to determine the effects of PP ingestion on daily MPS with and without RE in healthy women. In a single blind, parallel-group design, 24 young women (21 ± 3 years, n = 12/group) consumed a weight-maintaining baseline diet containing 0.8 g/kg/d of protein before being randomized to consume either 25 g of PP twice daily (1.6 g/kg/d total protein) or a control diet (CON) (0.8 g/kg/d total protein) for 2 wks. Unilateral RE (~30% of maximal strength to failure) was performed thrice weekly with the opposite limb serving as a non-exercised control (Rest). MPS was measured by deuterated water ingestion at baseline, following supplementation (Rest), and following supplementation + RE (Exercise). Ingestion of PP stimulated MPS by 0.14 ± 0.09 %/d at Rest, and by 0.32 ± 0.14 %/d in the Exercise limb. MPS was significantly elevated by 0.20 ± 0.11 %/d in the Exercise limb in CON (P = 0.008). Consuming PP to increase protein intake to levels twice the recommended dietary allowance for protein augmented rates of MPS. Performance of RE stimulated MPS regardless of protein intake. PP is a high-quality, plant-based protein supplement that augments MPS at rest and following RE in healthy young women.

The Impact of Step Reduction on Muscle Health in Aging: Protein and Exercise as Countermeasures.

Declines in strength and muscle function with age-sarcopenia-contribute to a variety of negative outcomes including an increased risk of: falls, fractures, hospitalization, and reduced mobility in older persons. Population-based estimates of the loss of muscle after age 60 show a loss of ~1% per year while strength loss is more rapid at ~3% per year. These rates are not, however, linear as periodic bouts of reduced physical activity and muscle disuse transiently accelerate loss of muscle and declines in muscle strength and power. Episodic complete muscle disuse can be due to sickness-related bed rest or local muscle disuse as a result of limb immobilization/surgery. Alternatively, relative muscle disuse occurs during inactivity due to illness and the associated convalescence resulting in marked reductions in daily steps, often referred to as step reduction (SR). While it is a "milder" form of disuse, it can have a similar adverse impact on skeletal muscle health. The physiological consequences of even short-term inactivity, modeled by SR, show losses in muscle mass and strength, as well as impaired insulin sensitivity and an increase in systemic inflammation. Though seemingly benign in comparison to bed rest, periodic inactivity likely occurs, we posit, more frequently with advancing age due to illness, declining mental health and declining mobility. Given that recovery from inactivity in older adults is slow or possibly incomplete we hypothesize that accumulated periods of inactivity contribute to sarcopenia. Periodic activity, even in small quantities, and protein supplementation may serve as effective strategies to offset the loss of muscle mass with aging, specifically during periods of inactivity. The aim of this review is to examine the recent literature encompassing SR, as a model of inactivity, and to explore the capacity of nutrition and exercise interventions to mitigate adverse physiological changes as a result of SR.

A Novel Amino Acid Composition Ameliorates Short-Term Muscle Disuse Atrophy in Healthy Young Men.

Skeletal muscle disuse leads to atrophy, declines in muscle function, and metabolic dysfunction that are often slow to recover. Strategies to mitigate these effects would be clinically relevant. In a double-blind randomized-controlled pilot trial, we examined the safety and tolerability as well as the atrophy mitigating effect of a novel amino acid composition (AXA2678), during single limb immobilization. Twenty healthy young men were randomly assigned (10 per group) to receive AXA2678 or an excipient- and energy-matched non-amino acid containing placebo (PL) for 28d: days 1-7, pre-immobilization; days 8-15, immobilization; and days 16-28 post-immobilization recovery. Muscle biopsies were taken on d1, d8 (immobilization start), d15 (immobilization end), and d28 (post-immobilization recovery). Magnetic resonance imaging (MRI) was utilized to assess quadriceps muscle volume (Mvol), muscle cross-sectional area (CSA), and muscle fat-fraction (FF: the fraction of muscle occupied by fat). Maximal voluntary leg isometric torque was assessed by dynamometry. Administration of AXA2678 attenuated muscle disuse atrophy compared to PL (p < 0.05) with changes from d8 to d15 in PL: ΔMvol = -2.4 ± 2.3% and ΔCSA = -3.1% ± 2.1%, both p < 0.001 vs. zero; against AXA2678: ΔMvol: -0.7 ± 1.8% and ΔCSA: -0.7 ± 2.1%, both p > 0.3 vs. zero; and p < 0.05 between treatment conditions for CSA. During immobilization, muscle FF increased in PL but not in AXA2678 (PL: 12.8 ± 6.1%, AXA2678: 0.4 ± 3.1%; p < 0.05). Immobilization resulted in similar reductions in peak leg isometric torque and change in time-to-peak (TTP) torque in both groups. Recovery (d15-d28) of peak torque and TTP torque was also not different between groups, but showed a trend for better recovery in the AXA2678 group. Thrice daily consumption of AXA2678 for 28d was found to be safe and well-tolerated. Additionally, AXA2678 attenuated atrophy, and attenuated accumulation of fat during short-term disuse. Further investigations on the administration of AXA2678 in conditions of muscle disuse are warranted. Clinical Trial Registration: https://clinicaltrials.gov, identifier: NCT03267745.

Temporal Response of Angiogenesis and Hypertrophy to Resistance Training in Young Men.

Although endurance exercise training promotes angiogenesis and improves metabolic health, the effect of resistance training on this process is less well defined. We hypothesized that capillarization would increase proportionally, and concurrently, with muscle fiber hypertrophy in response to resistance training in young men. METHODS: In this double-blind, randomized control trial, 36 men (22 ± 1 yr) were randomized to placebo or protein supplementation, and participated in 12 wk of resistance training. Skeletal muscle biopsies were collected before and after 2, 4, 8, and 12 wk of training. Immunohistochemistry assessed fiber type-specific size and capillarization. Western blot and reverse transcription polymerase chain reaction assessed proteins involved in the molecular regulation of angiogenesis. RESULTS: Resistance training effectively increased Type I (15% ± 4%; P < 0.01) and Type II fiber cross-sectional area (28% ± 5%; P < 0.0001), an effect that tended to be further enhanced with protein supplementation in Type II fibers (P = 0.078). Capillary-to-fiber ratio significantly increased in Type I (P = 0.001) and II (P = 0.015) fibers after 12 wk of resistance exercise training and was evident after only 2 wk. Capillary-to-fiber perimeter exchange index increased in the Type I fibers only (P = 0.054) after 12 wk of training. Training resulted in a reduction in vascular endothelial growth factor mRNA. A (P = 0.008), while vascular endothelial growth factor receptor 2 (P = 0.016), hypoxia-inducible factor 1α (P = 0.016), and endothelial nitric oxide synthase (P = 0.01) increased in both groups. Hypoxia-inducible factor 1α protein content was higher in the protein group (main group effect, P = 0.02), and endothelial nitric oxide synthase content demonstrated a divergent relationship (time-group interaction, P = 0.049). CONCLUSIONS: This study presents novel evidence that microvascular adaptations and the molecular pathways involved are elevated after 2 wk of a 12-wk resistance training program. Increases in muscle fiber cross-sectional area are effectively matched by the changes in the microvasculature, providing further support for resistance training programs to optimize metabolic health.

Resistance Training Increases Skeletal Muscle Capillarization in Healthy Older Men.

PURPOSE: Skeletal muscle capillarization plays a key role in oxygen and nutrient delivery to muscle. The loss of muscle mass with aging and the concept of anabolic resistance have been, at least partly, attributed to changes in skeletal muscle capillary structure and function. We aimed to compare skeletal muscle capillarization between young and older men and evaluate whether resistance-type exercise training increases muscle capillarization in older men. METHODS: Muscle biopsies were obtained from the vastus lateralis of healthy young (n = 14, 26 ± 2 yr) and older (n = 16, 72 ± 1 yr) adult men, with biopsies before and after 12 wk of resistance-type exercise training in the older subjects. Immunohistochemistry was used to assess skeletal muscle fiber size, capillary contacts (CC) per muscle fiber, and the capillary-to-fiber perimeter exchange (CFPE) index in type I and II muscle fibers. RESULTS: Type II muscle fibers were smaller in old versus young (4507 ± 268 vs 6084 ± 497 µm, respectively, P = 0.007). Type I and type II muscle fiber CC and CFPE index were smaller in old compared with young muscle (CC type I: 3.8 ± 0.2 vs 5.0 ± 0.3; CC type II: 3.2 ± 0.2 vs 4.2 ± 0.2, respectively; both P < 0.001). Resistance-type exercise training increased type II muscle fiber size only. In addition, CC and CFPE index increased in both the type I (26% ± 9% and 27% ± 8%) and type II muscle fibers (33% ± 7% and 24% ± 6%, respectively; all P ≤ 0.001) after 12 wk resistance training in older men. CONCLUSIONS: We conclude that resistance-type exercise training can effectively augment skeletal muscle fiber capillarization in older men. The greater capillary supply may be an important prerequisite to reverse anabolic resistance and support muscle hypertrophy during lifestyle interventions aiming to support healthy aging.

One Week of Bed Rest Leads to Substantial Muscle Atrophy and Induces Whole-Body Insulin Resistance in the Absence of Skeletal Muscle Lipid Accumulation.

Short (<10 days) periods of muscle disuse, often necessary for recovery from illness or injury, lead to various negative health consequences. The current study investigated mechanisms underlying disuse-induced insulin resistance, taking into account muscle atrophy. Ten healthy, young males (age: 23 ± 1 years; BMI: 23.0 ± 0.9 kg · m(-2)) were subjected to 1 week of strict bed rest. Prior to and after bed rest, lean body mass (dual-energy X-ray absorptiometry) and quadriceps cross-sectional area (CSA; computed tomography) were assessed, and peak oxygen uptake (VO2peak) and leg strength were determined. Whole-body insulin sensitivity was measured using a hyperinsulinemic-euglycemic clamp. Additionally, muscle biopsies were collected to assess muscle lipid (fraction) content and various markers of mitochondrial and vascular content. Bed rest resulted in 1.4 ± 0.2 kg lean tissue loss and a 3.2 ± 0.9% decline in quadriceps CSA (both P < 0.01). VO2peak and one-repetition maximum declined by 6.4 ± 2.3 (P < 0.05) and 6.9 ± 1.4% (P < 0.01), respectively. Bed rest induced a 29 ± 5% decrease in whole-body insulin sensitivity (P < 0.01). This was accompanied by a decline in muscle oxidative capacity, without alterations in skeletal muscle lipid content or saturation level, markers of oxidative stress, or capillary density. In conclusion, 1 week of bed rest substantially reduces skeletal muscle mass and lowers whole-body insulin sensitivity, without affecting mechanisms implicated in high-fat diet-induced insulin resistance.

High intensity interval and endurance training have opposing effects on markers of heart failure and cardiac remodeling in hypertensive rats.

There has been re-emerging interest and significant work dedicated to investigating the metabolic effects of high intensity interval training (HIIT) in recent years. HIIT is considered to be a time efficient alternative to classic endurance training (ET) that elicits similar metabolic responses in skeletal muscle. However, there is a lack of information on the impact of HIIT on cardiac muscle in disease. Therefore, we determined the efficacy of ET and HIIT to alter cardiac muscle characteristics involved in the development of diastolic dysfunction, such as ventricular hypertrophy, fibrosis and angiogenesis, in a well-established rodent model of hypertension-induced heart failure before the development of overt heart failure. ET decreased left ventricle fibrosis by ~40% (P < 0.05), and promoted a 20% (P<0.05) increase in the left ventricular capillary/fibre ratio, an increase in endothelial nitric oxide synthase protein (P<0.05), and a decrease in hypoxia inducible factor 1 alpha protein content (P<0.05). In contrast, HIIT did not decrease existing fibrosis, and HIIT animals displayed a 20% increase in left ventricular mass (P<0.05) and a 20% decrease in cross sectional area (P<0.05). HIIT also increased brain natriuretic peptide by 50% (P<0.05), in the absence of concomitant angiogenesis, strongly suggesting pathological cardiac remodeling. The current data support the longstanding belief in the effectiveness of ET in hypertension. However, HIIT promoted a pathological adaptation in the left ventricle in the presence of hypertension, highlighting the need for further research on the widespread effects of HIIT in the presence of disease.

Cardiac rehabilitation wait times: effect on enrollment.

PURPOSE: Cardiac rehabilitation (CR) is a proven effective means for secondary prevention of coronary heart disease. Timely access to CR services is key to promoting patient participation and ensuring optimal patient outcomes. Despite wait time benchmarks having been established, research regarding how long patients wait to enter CR following referral receipt is limited. The aim of this study was to (a) describe wait times from CR referral to intake assessment and (b) examine the association of wait time to CR enrollment rates. METHODS: Wait time from date of CR referral to date of intake assessment was calculated in days for 599 participants referred to CR from 2006 to 2009 inclusive. A descriptive examination of sociodemographic and clinical characteristics was performed, followed by logistic regression analysis to assess the wait time by enrollment relationship. RESULTS: Median wait time from referral receipt to CR intake was 42.0 days. Wait time had a negative effect on CR enrollment, such that for every 1-day increment in wait time, patients were 1% less likely to enroll. CONCLUSIONS: The time that patients wait to enroll in CR may affect the number of patients who choose to attend, and longer wait times may mean fewer patients will benefit from CR participation. Programs should be encouraged to undertake quality improvement initiatives to ensure wait times are not negatively impacting patient enrollment and ultimately preventing patients from benefiting from CR participation. Further research is needed to establish evidence-based wait time benchmarks and interventions to promote timely access to CR services.