Reduced Muscle Oxidative Capacity Research Articles

Alteration of skeletal muscle energy metabolism assessed by 31 P MRS in clinical routine: Part 2. Clinical application.

In this second part of a two-part paper, we intend to demonstrate the impact of the previously proposed advanced quality control pipeline. To understand its benefit and challenge the proposed methodology in a real scenario, we chose to compare the outcome when applying it to the analysis of two patient populations with significant but highly different types of fatigue: COVID-19 and multiple sclerosis (MS). 31 P-MRS was performed on a 3 T clinical MRI, in 19 COVID-19 patients, 38 MS patients, and 40 matched healthy controls. Dynamic acquisitions using an MR-compatible ergometer ran over a rest (40 s), exercise (2 min), and a recovery phase (6 min). Long and short TR acquisitions were also made at rest for T1 correction. The advanced data quality control pipeline presented in Part 1 is applied to the selected patient cohorts to investigate its impact on clinical outcomes. We first used power and sample size analysis to estimate objectively the impact of adding the quality control score (QCS). Then, comparisons between patients and healthy control groups using the validated QCS were performed using unpaired t tests or Mann-Whitney tests (p < 0.05). The application of the QCS resulted in increased statistical power, changed the values of several outcome measures, and reduced variability (standard deviation). A significant difference was found between the T1PCr and T1Pi values of MS patients and healthy controls. Furthermore, the use of a fixed correction factor led to systematically higher estimated concentrations of PCr and Pi than when using individually corrected factors. We observed significant differences between the two patient populations and healthy controls for resting [PCr]-MS only, [Pi ], [ADP], [H2 PO4 - ], and pH-COVID-19 only, and post-exercise [PCr], [Pi ], and [H2 PO4 - ]-MS only. The dynamic indicators τPCr , τPi , ViPCr , and Vmax were reduced for COVID-19 and MS patients compared with controls. Our results show that QCS in dynamic 31 P-MRS studies results in smaller data variability and therefore impacts study sample size and power. Although QCS resulted in discarded data and therefore reduced the acceptable data and subject numbers, this rigorous and unbiased approach allowed for proper assessment of muscle metabolites and metabolism in patient populations. The outcomes include an increased metabolite T1 , which directly affects the T1 correction factor applied to the amplitudes of the metabolite, and a prolonged τPCr , indicating reduced muscle oxidative capacity for patients with MS and COVID-19.

Reduced Muscle Oxidative Capacity During and After Exercise in Older Adults With Obesity

Abstract Objective: Obesity and physical activity are two major factors affecting aerobic performance in older adults. The underlying mechanisms of the causes are still unknown. Oxidative capacity, muscles’ maximal capacity to utilize oxygen, is a part of aerobic performance. Muscle oxygen level (SmO2), a measure of oxidative capacity, reflects the balance between oxygen delivery and oxygen demand. When oxygen delivery surpasses oxygen demand, SmO2 increases, which indicates higher oxidative capacity. This study aimed to identify the influence of obesity and physical activity level on SmO2 changes during and after short exercise. Methods: This is a cross-sectional study. SmO2 changes during and after a bilateral heel-raise (BHR) test were measured in 60 community-dwelling older adults (≥ 60 years old) in four groups: inactive obese, active obese, inactive non-obese, and active non-obese. Inactive is defined as performing less than 150 minutes/week moderate-intensity activity. Results: The inactive obese group took a longer time for SmO2 drop during the BHR test, had a lower SmO2 level at the end, and recovered slower after the test than all other groups. Especially, compared with the active non-obese group, this group exhibited significantly poorer SmO2 recovery one minute after the test, 5.3% less (p=.036). The active obese group’s oxidative capacity was similar to the inactive non-obese group, although lower than the active non-obese group. Discussion: To prevent physical decline in older adults with obesity, regular exercise has been recommended. This study substantiated this from a hemodynamics viewpoint. Older adults with obesity need 150+ minutes/week moderate-intensity exercise.

Preserved skeletal muscle oxidative capacity in older adults despite decreased cardiorespiratory fitness with ageing.

Healthy older adults exhibit lower cardiorespiratory fitness ( ) than young in the absence of any age-related difference in skeletal muscle mitochondrial capacity, suggesting central haemodynamics plays a larger role in age-related declines in . Total physical activity did not differ by age, but moderate-to-vigorous physical activity was lower in older compared to young adults. Moderate-to-vigorous physical activity is associated with and muscle oxidative capacity, but physical inactivity cannot entirely explain the age-related reduction in . Declining fitness ( ) is a hallmark of ageing and believed to arise from decreased oxygen delivery and reduced muscle oxidative capacity. Physical activity is a modifiable lifestyle factor that is critical when evaluating the effects of age on parameters of fitness and energy metabolism. The objective was to evaluate the effects of age and sex on , muscle mitochondrial physiology, and physical activity in young and older adults. An additional objective was to assess the contribution of skeletal muscle oxidative capacity to age-related reductions in and determine if age-related variation in and muscle oxidative capacity could be explained on the basis of physical activity levels. In 23 young and 52 older men and women measurements were made of , mitochondrial physiology in permeabilized muscle fibres, and free-living physical activity by accelerometry. Regression analyses were used to evaluate associations between age and , mitochondrial function, and physical activity. Significant age-related reductions were observed for (P<0.001), but not muscle mitochondrial capacity. Total daily step counts did not decrease with age, but older adults showed lower moderate-to-vigorous physical activity, which was associated with (R2 =0.323, P<0.001) and muscle oxidative capacity (R2 =0.086, P=0.011). After adjusting for sex and physical activity, age was negatively associated with but not muscle oxidative capacity. Healthy older adults exhibit lower but preserved mitochondrial capacity compared to young. Physical activity, particularly moderate-to-vigorous, is a key factor in observed age-related changes in fitness and muscle oxidative capacity, but cannot entirely explain the age-related reduction in .

Adipose tissue macrophage populations and inflammation are associated with systemic inflammation and insulin resistance in obesity.

Obesity is accompanied by numerous systemic and tissue-specific derangements, including systemic inflammation, insulin resistance, and mitochondrial abnormalities in skeletal muscle. Despite growing recognition that adipose tissue dysfunction plays a role in obesity-related disorders, the relationship between adipose tissue inflammation and other pathological features of obesity is not well-understood. We assessed macrophage populations and measured the expression of inflammatory cytokines in abdominal adipose tissue biopsies in 39 nondiabetic adults across a range of body mass indexes (BMI 20.5-45.8 kg/m2). Skeletal muscle biopsies were used to evaluate mitochondrial respiratory capacity, ATP production capacity, coupling, and reactive oxygen species production. Insulin sensitivity (SI) and β cell responsivity were determined from test meal postprandial glucose, insulin, c-peptide, and triglyceride kinetics. We examined the relationships between adipose tissue inflammatory markers, systemic inflammatory markers, SI, and skeletal muscle mitochondrial physiology. BMI was associated with increased adipose tissue and systemic inflammation, reduced SI, and reduced skeletal muscle mitochondrial oxidative capacity. Adipose-resident macrophage numbers were positively associated with circulating inflammatory markers, including tumor necrosis factor-α (TNFα) and C-reactive protein (CRP). Local adipose tissue inflammation and circulating concentrations of TNFα and CRP were negatively associated with SI, and circulating concentrations of TNFα and CRP were also negatively associated with skeletal muscle oxidative capacity. These results demonstrate that obese humans exhibit increased adipose tissue inflammation concurrently with increased systemic inflammation, reduced insulin sensitivity, and reduced muscle oxidative capacity and suggest that adipose tissue and systemic inflammation may drive obesity-associated metabolic derangements.NEW AND NOTEWORTHY Adipose inflammation is proposed to be at the nexus of the systemic inflammation and metabolic derangements associated with obesity. The present study provides evidence to support adipose inflammation as a central feature of the pathophysiology of obesity. Adipose inflammation is associated with systemic and peripheral metabolic derangements, including increased systemic inflammation, reduced insulin sensitivity, and reduced skeletal muscle mitochondrial respiration.

The impact of statin therapy and aerobic exercise training on skeletal muscle and whole-body aerobic capacity

BackgroundStatin use is widely recognized for improving cardiovascular health, but questions remain on how statin use influences skeletal muscle, particularly mitochondrial function. Study objective, design and participantsThe influence of statin therapy and exercise (EX) on aerobic capacity was determined. In Study1, skeletal muscle aerobic capacity was measured before and after 80 mg atorvastatin therapy. In Study2, aerobic capacity (skeletal muscle and whole body) was measured before and after a 12-week exercise randomized control trial in older adults (age = 67 ± 5 yrs.), a subset of which were on chronic low-moderate intensity statin therapy. Main outcome measuresMuscle oxidative capacity was determined from the phosphocreatine recovery rate constant (kPCr) using 31P Magnetic Resonance Spectroscopy. Whole body peak oxygen uptake (VO2 peak) was measured during a graded exercise test with indirect calorimetry. ResultsHigh dose statin therapy resulted in a 12% reduction in muscle oxidative capacity (pre = 1.34 ± 0.34 min−1, post = 1.17 ± 0.25 min−1, p = 0.004). Similarly, chronic low-moderate dose statin therapy was associated with lower muscle oxidative capacity at baseline (1.50 ± 0.35 min−1) compared to non-statin users (1.88 ± 0.047 min−1, p = 0.019). Following EX, muscle oxidative capacity increased by 35–40% (statin: Pre: 1.39 ± 0.44 vs. Post: 1.88 ± 0.47 min−1, no statin Pre: 1.86 ± 0.58 vs. Post: 2.58 ± 0.85 min−1) compared to control groups (Pre: 1.74 ± 0.27 vs Post: 1.75 ± 0.49 min−1, p = 0.001). VO2 peak increased by 11% for EX groups (Pre: 18.8 ± 2.8 vs. Post: 20.8 ± 3.0 ml·kg−1·min−1) following training compared to a small decline in controls (Pre: 21.8 ± 3.7 vs. Post: 20.8 ± 3.04 ml·kg−1·min−1, p = 0.001). ConclusionsStatin therapy resulted in reduced muscle oxidative capacity. Aerobic exercise improved skeletal muscle oxidative capacity and whole-body aerobic capacity during statin therapy.

Muscle Dysfunction and Walking Impairment in Women with Multiple Sclerosis.

Recent evidence suggests that skeletal muscle dysfunction is involved in disability progression in people with multiple sclerosis (MS). However, the relationship between muscle dysfunction and walking impairments in MS remains unclear. Thus, the cross-sectional relationships between muscle-specific oxidative capacity and walking endurance in women with MS were evaluated. Twenty women with MS (11 African American, 9 white) were tested. Muscle oxidative capacity of the medial gastrocnemius was measured using near-infrared spectroscopy after electrical stimulation. Muscle endurance was evaluated using accelerometer-based mechanomyography during electrical stimulation. Muscle strength was measured during maximal voluntary plantarflexion using handheld dynamometry. Walking function was measured using the Timed 25-Foot Walk test and the 6-Minute Walk Test (6MWT). Reduced muscle oxidative capacity (R 2 = 0.68-0.71, P < .01) and muscle endurance (R 2 = 0.59-0.78, P < .01) were associated with lower Timed 25-Foot Walk time and 6MWT distance. Muscle strength was weakly correlated to 6MWT distance (R 2 = 0.21, P = .02). No differences in muscle function or clinical outcome measures were found between African American and white subgroups. Women with moderate-to-severe disability (Expanded Disability Status Scale [EDSS] score, 5.0-6.5) had significantly reduced muscle oxidative capacity, muscle endurance, and walking ability compared with women with mild disability (EDSS score, 2.5-4.5). Reductions in muscle function in people with MS are related to declines in walking function across all levels of disability. Muscle dysfunction is not differentially related to walking impairment in African American and white women with MS.

Offspring of Mothers with Diabetes have Reduced Muscle Oxidative Capacity Measured by Near Infrared Spectroscopy

Adult offspring of mothers with type 2 diabetes have been reported to have reduced skeletal muscle mitochondrial oxidative capacity (OXPHOS) using in vivo31P-Magnetic Resonance Spectroscopy (31P-MRS). Near Infrared Spectroscopy (NIRS) also has the capability of measuring skeletal muscle OXPHOS, and provides indices of skeletal OXPHOS comparable to 31P-MRS. Moreover, the cost of measuring skeletal muscle OXPHOS by NIRS is substantially less than by 31P-MRS. PURPOSE: To determine whether NIRS could detect OXPHOS differences in adult offspring of mothers with type 2 diabetes (n=8) compared to controls (n=9). METHODS: Using continuous-wave NIRS (Artinis, Oxymon) coupled with transient arterial occlusions (~ 300 mm Hg, 5 on/5 off x 9, 10 on/10 off x 11), we measured muscle oxygen consumption (mVO2) in the vastus lateralis following a 7 sec maximal isometric knee extension performed in the supine position. We express the mVO2 as a percent per second (%/s), relative to an ischemic calibration. We fit the recovery mVO2 following the isometric contraction to an exponential curve using custom routines written in MATLAB by Terence Ryan to calculate the time constant (Tc) for the recovery of mVO2, which is an index of mitochondrial OXPHOS. These routines also help correct for changes in blood volume that occur during the atrial occlusion. We also measured peak oxygen uptake (VO2peak) using a standardized incremental exercise test with indirect calorimetry on a cycle ergometer. RESULTS: Age (21±1 vs. 21±2 y, p>0.05), BMI (24±3 vs. 23±2 kg/m2, p>0.05), and VO peak (32±4 vs. 32±5 ml[BULLET OPERATOR]kg-1[BULLET OPERATOR]min-1, p>0.05) were similar between offspring and controls. In contrast, offspring had higher recovery Tc compared to controls (47±24 vs. 28±10 sec, p<0.05) suggestive of reduced OXPHOS. CONCLUSIONS: Our results support the use of NIRS to measure expected differences in skeletal muscle OXPHOS between offspring and controls. Of interest, we also found that the Tc measured in the offspring to have a greater degree of variability than controls suggesting the potential for prescribing therapeutic interventions early to possibly reduce incidence of type 2 diabetes. The present study was funded in part by the Robert and Patricia Hines Endowed Professorship in Kinesiology, LSU and a College of Human Sciences and Education Dean’s Circle Grant.

Physical activity unveils the relationship between mitochondrial energetics, muscle quality, and physical function in older adults.

BackgroundThe concept of mitochondrial dysfunction in ageing muscle is highly controversial. In addition, emerging evidence suggests that reduced muscle oxidative capacity and efficiency underlie the aetiology of mobility loss in older adults. Here, we hypothesized that studying well‐phenotyped older cohorts across a wide range of physical activity would unveil a range of mitochondrial function in skeletal muscle and in turn allow us to more clearly examine the impact of age per se on mitochondrial energetics. This also enabled us to more clearly define the relationships between mitochondrial energetics and muscle lipid content with clinically relevant assessments of muscle and physical function.MethodsThirty‐nine volunteers were recruited to the following study groups: young active (YA, n = 2 women/8 men, age = 31.2 ± 5.4 years), older active (OA, n = 2 women/8 men, age = 67.5 ± 2.7 years), and older sedentary (OS, n = 8 women/11 men, age = 70.7 ± 4.7 years). Participants completed a graded exercise test to determine fitness (VO2peak), a submaximal exercise test to determine exercise efficiency, and daily physical activity was recorded using a tri‐axial armband accelerometer. Mitochondrial energetics were determined by (i) 31P magnetic resonance spectroscopy and (ii) respirometry of fibre bundles from vastus lateralis biopsies. Quadriceps function was assessed by isokinetic dynamometry and physical function by the short physical performance battery and stair climb test.ResultsDaily physical activity energy expenditure was significantly lower in OS, compared with YA and OA groups. Despite fitness being higher in YA compared with OA and OS, mitochondrial respiration, maximum mitochondrial capacity, Maximal ATP production/Oxygen consumption (P/O) ratio, and exercise efficiency were similar in YA and OA groups and were significantly lower in OS. P/O ratio was correlated with exercise efficiency. Time to complete the stair climb and repeated chair stand tests were significantly greater for OS. Interestingly, maximum mitochondrial capacity was related to muscle contractile performance and physical function.ConclusionsOlder adults who maintain a high amount of physical activity have better mitochondrial capacity, similar to highly active younger adults, and this is related to their better muscle quality, exercise efficiency, and physical performance. This suggests that mitochondria could be an important therapeutic target for sedentary ageing associated conditions including sarcopenia, dynapenia, and loss of physical function.

Impaired Muscle Oxygenation and Elevated Exercise Blood Pressure in Hypertensive Patients: Links With Vascular Stiffness.

This study examined in vivo (1) skeletal muscle oxygenation and microvascular function, at rest and during handgrip exercise, and (2) their association with macrovascular function and exercise blood pressure (BP), in newly diagnosed, never-treated patients with hypertension and normotensive individuals. Ninety-one individuals (51 hypertensives and 40 normotensives) underwent office and 24-hour ambulatory BP, arterial stiffness, and central aortic BP assessment, followed by a 5-minute arterial occlusion and a 3-minute submaximal handgrip exercise. Changes in muscle oxygenated and deoxygenated hemoglobin and tissue oxygen saturation were continuously monitored by near-infrared spectroscopy and beat-by-beat BP by Finapres. Hypertensives had higher (P<0.001) central aortic BP and pulse wave velocity versus normotensives and exhibited (1) a blunted tissue oxygen saturation response during occlusion, with slower (P=0.006) deoxygenation rate, suggesting reduced muscle oxidative capacity, and (2) a slower reoxygenation rate and blunted hyperemic response (P<0.05), showing reduced microvascular reactivity. Muscle oxygenation responses were correlated with aortic systolic and pulse pressure and augmentation index (P<0.05; age and body mass index (BMI) adjusted). When exercising at the same submaximal intensity, hypertensives required a significantly greater (P<0.001) increase in BP for achieving similar muscle oxygenation levels as normotensives. This response was correlated with the magnitude of microvascular hyperemia and aortic BP. In conclusion, nontreated patients with hypertension exhibit prominent reductions in in vivo indices of skeletal muscle oxidative capacity, suggestive of mitochondrial dysfunction, and blunted muscle microvascular reactivity. These dysfunctions were associated with higher aortic systolic BP and arterial stiffness. Dysregulations in muscle oxygen delivery/utilization and microvascular stiffness, in hypertensive patients, partially contribute to their exaggerated BP during exercise.

Walking performance is positively correlated to calf muscle fiber size in peripheral artery disease subjects, but fibers show aberrant mitophagy: an observational study.

BackgroundPatients with lower extremity peripheral artery disease (PAD) have decreased mobility, which is not fully explained by impaired blood supply to the lower limb. Additionally, reports are conflicted regarding fiber type distribution patterns in PAD, but agree that skeletal muscle mitochondrial respiration is impaired.MethodsTo test the hypothesis that reduced muscle fiber oxidative activity and type I distribution are negatively associated with walking performance in PAD, calf muscle biopsies from non-PAD (n = 7) and PAD participants (n = 26) were analyzed immunohistochemically for fiber type and size, oxidative activity, markers of autophagy, and capillary density. Data were analyzed using analysis of covariance.ResultsThere was a wide range in fiber type distribution among subjects with PAD (9–81 % type I fibers) that did not correlate with walking performance. However, mean type I fiber size correlated with 4-min normal- and fastest-paced walk velocity (r = 0.4940, P = 0.010 and r = 0.4944, P = 0.010, respectively). Although intensity of succinate dehydrogenase activity staining was consistent with fiber type, up to 17 % of oxidative fibers were devoid of mitochondria in their cores, and the core showed accumulation of the autophagic marker, LC3, which did not completely co-localize with LAMP2, a lysosome marker.ConclusionsCalf muscle type I fiber size positively correlates with walking performance in PAD. Accumulation of LC3 and a lack of co-localization of LC3 with LAMP2 in the area depleted of mitochondria in PAD fibers suggests impaired clearance of damaged mitochondria, which may contribute to reduced muscle oxidative capacity. Further study is needed to determine whether defective mitophagy is associated with decline in function over time, and whether interventions aimed at preserving mitochondrial function and improving autophagy can improve walking performance in PAD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1030-6) contains supplementary material, which is available to authorized users.

Training improves the oxidative phenotype of muscle during the transition from cardiac hypertrophy to heart failure without altering MyoD and myogenin.

What is the central question of this study? We investigated the effects of physical training on phenotypic (fibre-type content) and myogenic features (MyoD and myogenin expression) in skeletal muscle during the transition from cardiac hypertrophy to heart failure. What is the main finding and its importance? We provide new insight into skeletal muscle adaptations by showing that physical training increases the type I fibre content during the transition from cardiac hypertrophy to heart failure, without altering MyoD and myogenin expression. These results have important clinical implications for patients with heart failure, because this population has reduced muscle oxidative capacity. The purpose of this study was to investigate the effects of physical training (PT) on phenotypic features (fibre-type content) and myogenic regulatory factors (MyoD and myogenin) in rat skeletal muscle during the transition from cardiac hypertrophy to heart failure. We used the model of ascending aortic stenosis (AS) to induce heart failure in male Wistar rats. Sham-operated animals were used as age-matched controls. At 18weeks after surgery, rats with ventricular dysfunction were randomized into the following four groups: sham-operated, untrained (Sham-U; n=8); sham-operated, trained (Sham-T; n=6); aortic stenosis, untrained (AS-U; n=6); and aortic stenosis, trained (AS-T; n=8). The AS-T and Sham-T groups were submitted to a 10week aerobic PT programme, while the AS-U and Sham-U groups remained untrained for the same period of time. After the PT programme, the animals were killed and the soleus muscles collected for phenotypic and molecular analyses. Physical training promoted type IIa-to-I fibre conversion in the trained groups (Sham-T and AS-T) compared with the untrained groups (Sham-U and AS-U). No significant (P>0.05) differences were found in type I or IIa fibre content in the AS-U group compared with the Sham-U group. Additionally, there were no significant (P>0.05) differences in the myogenic regulatory factors MyoD and myogenin (gene and protein) expression between the groups. Therefore, our results indicate that PT may be a suitable strategy to improve the oxidative phenotype in skeletal muscle during the transition from cardiac hypertrophy to heart failure, without altering MyoD and myogenin.

Reduced skeletal muscle oxidative capacity and elevated ceramide but not diacylglycerol content in severe obesity

The link between a reduced capacity for skeletal muscle mitochondrial fatty acid oxidation (FAO) and lipotoxicity in human insulin resistance has been the subject of intense debate. The objective of this study was to investigate whether reduced FAO is associated with elevated acyl CoA, ceramide, and diacylglycerol (DAG) in severely obese insulin resistant subjects. Muscle biopsies were conducted in lean (L, 22.6 ± 0.5 kg/m(2) , n = 8), Class I (CI, 32.1 ± 0.4 kg/m(2) , n = 7) and Class II&III obese (CII&III, 45.6 ± 1.1 kg/m(2) , n = 15) women for acyl CoA, sphingolipid and DAG profiling. Intramyocellular triglyceride (IMTG) content was determined by histology. FAO was assessed by incubating muscle homogenates with [1-C]palmitate and measuring CO2 production. Cardiolipin content was quantified as an index of mitochondrial content. Lipid metabolism proteins, DGAT1, PLIN5, and PNPLA2 were quantified in biopsy samples by western blot. CII&III were more insulin resistant (HOMA-IR: 4.5 ± 0.5 vs. 1.1 ± 0.1, P < 0.001), and had lower FAO (∼58%, P = 0.007) and cardiolipin content (∼31%, P = 0.013) compared to L. IMTG was elevated in CI (P = 0.04) and CII&III (P = 0.04) compared to L. Sphingolipid content was higher in CII&III compared to L (13.6 ± 1.1 vs. 10.3 ± 0.5 pmol/mg, P = 0.031) whereas DAG content was not different among groups. DGAT1 was elevated in CII&III, and PLIN5 was elevated in CI compared to L. Severe obesity is associated with reduced muscle oxidative capacity and occurs concomitantly with elevated IMTG, ceramide and insulin resistance.

Reduced muscle oxidative capacity is independent of O2 availability in elderly people

Impaired O2 transport to skeletal muscle potentially contributes to the decline in aerobic capacity with aging. Thus, we examined whether (1) skeletal muscle oxidative capacity decreases with age and (2) O2 availability or mitochondrial capacity limits the maximal rate of mitochondrial ATP synthesis in vivo in sedentary elderly individuals. We used (31)P-magnetic resonance spectroscopy ((31)P-MRS) to examine the PCr recovery kinetics in six young (26 ± 10 years) and six older (69 ± 3 years) sedentary subjects following 4 min of dynamic plantar flexion exercise under different fractions of inspired O2 (FiO2, normoxia 0.2; hyperoxia 1.0). End-exercise pH was not significantly different between old (7.04 ± 0.10) and young (7.05 ± 0.04) and was not affected by breathing hyperoxia (old 7.08 ± 0.08, P > 0.05 and young 7.05 ± 0.03). Likewise, end-exercise PCr was not significantly different between old (19 ± 4 mM) and young (24 ± 5 mM) and was not changed in hyperoxia. The PCr recovery time constant was significantly longer in the old (36 ± 9 s) compared to the young in normoxia (23 ± 8 s, P < 0.05) and was not significantly altered by breathing hyperoxia in both the old (35 ± 9 s) and young (29 ± 10 s) groups. Therefore, this study reveals that the muscle oxidative capacity of both sedentary young and old individuals is independent of O2 availability and that the decline in oxidative capacity with age is most likely due to limited mitochondrial content and/or mitochondrial dysfunction and not O2 availability.

Deficiency of electron transport chain in human skeletal muscle mitochondria in type 2 diabetes mellitus and obesity

Insulin resistance in skeletal muscle in obesity and T2DM is associated with reduced muscle oxidative capacity, reduced expression in nuclear genes responsible for oxidative metabolism, and reduced activity of mitochondrial electron transport chain. The presented study was undertaken to analyze mitochondrial content and mitochondrial enzyme profile in skeletal muscle of sedentary lean individuals and to compare that with our previous data on obese or obese T2DM group. Frozen skeletal muscle biopsies obtained from lean volunteers were used to estimate cardiolipin content, mtDNA (markers of mitochondrial mass), NADH oxidase activity of mitochondrial electron transport chain (ETC), and activity of citrate synthase and beta-hydroxyacyl-CoA dehydrogenase (beta-HAD), key enzymes of TCA cycle and beta-oxidation pathway, respectively. Frozen biopsies collected from obese or T2DM individuals in our previous studies were used to estimate activity of beta-HAD. The obtained data were complemented by data from our previous studies and statistically analyzed to compare mitochondrial content and mitochondrial enzyme profile in lean, obese, or T2DM cohort. The total activity of NADH oxidase was reduced significantly in obese or T2DM subjects. The cardiolipin content for lean or obese group was similar, and although for T2DM group cardiolipin showed a tendency to decline, it was statistically insignificant. The total activity of citrate synthase for lean and T2DM group was similar; however, it was increased significantly in the obese group. Activity of beta-HAD and mtDNA content was similar for all three groups. We conclude that the total activity of NADH oxidase in biopsy for lean group is significantly higher than corresponding activity for obese or T2DM cohort. The specific activity of NADH oxidase (per mg cardiolipin) and NADH oxidase/citrate synthase and NADH oxidase/beta-HAD ratios are reduced two- to threefold in both T2DM and obesity.

Skeletal muscle endurance and muscle metabolism in patients with chronic heart failure

Alterations in skeletal muscle function are known to contribute to exercise intolerance in patients with chronic heart failure (CHF). To evaluate whether muscle isometric endurance can be objectively measured and whether it is related to skeletal muscle metabolism in CHF. Isometric endurance of the vastus lateralis, measured as time to fatigue (T(F)), was evaluated in 25 patients with CHF (55+/-8 years of age [mean +/- SD]) and 18 healthy subjects (HS) (62+/-6 years of age [mean +/- SD]). Median frequency of surface electromyography was obtained from spectral analysis using a fast Fourier transformation. Citrate synthase (CS), 3-hydroxyacyl-CoA dehydrogenase (HADH), hexokinase (HK) and phosphofructokinase (PFK) activities were determined from the right vastus lateralis muscle. T(F) was lower in CHF patients than in HS (49+/-4 s and 80+/-7 s, respectively; P<0.01). Muscle fatigue was present at the end of the endurance test in both groups (median frequency breakpoint at mid-exercise for both groups [P<0.05]). CS (P<0.01) and HK (P<0.01) activities were lower in CHF patients than in HS, but PFK activity was higher (P<0.05). T(F) correlated significantly with CS (r=0.50), HADH (r=0.42), PFK (r=-0.47) and HK (r=0.41) activities and the PFK/CS ratio (r=-0.39) when both groups were considered, and with HADH (r=0.47) and PFK (r=-0.57) activities for the CHF group alone (all P<0.05). These results suggest that isometric endurance of the vastus lateralis muscle is reduced in patients with CHF and that it is related to a reduced muscle oxidative capacity.

The Physiological Response to Exercise in Chronic Fatigue Syndrome

Background: The chronic fatigue syndrome (CFS) is characterised by a limited exercise capacity. Studies have reported reduced muscle oxidative capacity in CFS, evidenced by abnormal acidosis during exercise and reduced aerobic capacity and exercise endit ranee.Objective: To compare physiological responses to walking exercise in CFS subjects, sedentary controls, and clinically improved CFS subjects.Design: Age- and sex-matched pairs, with repeated measures.Subjects: Sixteen subjects diagnosed with CFS and 16 age- and sex-matched sedentary controls.Measurements: Heart rate (HR), oxygen uptake (V02) ventilation (VE) and relative perceived exertion (RPE) responses to incremental walking exercise to volitional exhaustion.Results: CFS subjects reached significantly lower HRpeak (P = 0.023) and achieved nonsignificantly (P > 0.05) lower TO2penk than control subjects. Despite no differences in submaximal exercise responses, CFS subjects reported higher RPE scores than controls (P = 0,003) at submaximal workloads. RPE scores correlated with symptomatic scores for emotionality (r = 0.642) and general fatigue (r = 0.568). Symptomatic recovery in six CFS subjects was associated with nonsignificant increases in HRpeak, VO2peak and VEpeak and nonsignificant decreases in RPE scores at submaximal workloads.Conclusions: These data suggested that the limited exercise capacity in CFS subjects may be explained by deconditioning due to the sedentary lifestyle necessitated by the condition, coupled with an increased perception of exertion, potentially linked to psychological symptoms associated with CFS.

Skeletal muscle glycolytic and oxidative enzyme capacities are determinants of insulin sensitivity and muscle composition in obese women

Regional fat distribution is an important determinant of insulin resistance in obesity. In the current study, the relationship between skeletal muscle insulin sensitivity, mid-thigh muscle composition, and the metabolic profile of muscle was investigated. Muscle composition was assessed by computed tomography of the mid-thigh, and by activities of marker enzymes of aerobic-oxidative and glycolytic pathways and muscle fiber typing using biopsies of the vastus lateralis muscle. Muscle with reduced Hounsfield attenuation on computed tomography scans was increased in proportion to obesity, and was strongly related to insulin resistance, reduced muscle oxidative capacity, and increased anaerobic and glycolytic capacities by muscle. These findings suggest that as part of its expression of insulin resistance, skeletal muscle of obese individuals is also poorly equipped for substrate oxidation and manifests increased storage of fat.

Aging Skeletal Muscle

The mass of many weight-bearing muscles declines in old rats, secondary to the atrophy of fibers, particularly of type IIb, with relatively little loss of muscle fibers during most of the adult life span. In humans, muscle atrophy is the result of a combination of progressive fiber loss and fiber atrophy. In both species, the proportion of histochemically determined fiber types is relatively stable across the adult portion of the life span. The loss of strength in old age is predominantly accounted for by reduced muscle mass in humans and rats. Resistance training leads to increased muscle mass and strength in old humans and rats, primarily by increasing fiber CSA. Muscle capillarity is unchanged in old rats but decreases in old dogs. Apparently, capillarity declines in truly sedentary older people. Endurance training enhances capillarity, and old rats and humans can attain levels of capillarity comparable to their active young counterparts, even when performing considerably less exercise. Blood flow during contractile activity is reduced in male rats and humans but not in old female rats or dogs. Oxidative capacity declines in many muscles of sedentary old rats and humans. With endurance training, old individuals from both species attain levels of muscle oxidative capacity quite similar to those in identically training young individuals. Muscle insulin-stimulated glucose transport is enhanced in rats after a bout of exercise, regardless of age. Endurance training elevates muscle GLUT-4 levels in young and middle-aged, but not old, rats, perhaps because the old rats trained at slower treadmill speeds. Middle-aged (47-62 yr) men and women can substantially increase muscle GLUT-4 with relatively brief (12-14 wk) endurance training; older humans (> 70-80 yr) have not been studied. Endurance training leads to reduced LDH activity without altering PFK or phosphorylase in old rats and humans. Muscle glycogen depletion, CP depletion, and lactate accumulation during contractile activity are exaggerated in old rats, apparently secondary to reduced muscle oxidative capacity and blood flow. Resting muscle glycogen concentration is diminished in older humans, probably in part because of a more sedentary lifestyle. Although several months of endurance training raises muscle glycogen concentration in older people, it does not restore it to youthful levels. Endurance training can greatly improve endurance in old age, at least in part by the same mechanism originally described in youth, i.e., an increase in muscle oxidative capacity, which contributes to reduced glycogen depletion.(ABSTRACT TRUNCATED AT 400 WORDS)

Impact of reduced cytochrome oxidase activity on peak oxygen consumption of muscle

The impact of reduced muscle oxidative capacity on peak oxygen consumption and isometric performance was evaluated using an isolated rat hindlimb preparation perfused with a high oxygen delivery. Capacity for electron transport was reduced with chloramphenicol (CAP), an inhibitor of mitochondrial gene-coded protein synthesis. The activity of cytochrome oxidase, a mitochondrial cristae component, was reduced approximately 45% (P less than 0.005) in the mixed-fiber-type plantaris muscle. Several facets of muscle remodeling were also evident with the 10- to 14-day CAP treatment, including decreased citrate synthase activity, increased capillarity, and increased numbers of type IIc fibers. Perfusion of CAP (n = 6) and control (n = 7) rat hindlimbs of similar size with similar total flows (10-11 ml/min) and oxygen contents (20-21 vol%) resulted in similarly high oxygen deliveries to contracting muscles of the hindlimbs (CAP, 9.66 +/- 0.83 mumols.min-1.g-1; control, 8.74 +/- 0.75). Performance of the gastrocnemius-plantaris-soleus group declined in a similar fashion for both groups during increasingly intense near-steady-state tetanic contraction (100 ms at 100 Hz) conditions of 4, 8, 15, 30, 45, and 60 per minute. Oxygen consumption was similar for both groups at rest and increased similarly at each contraction condition. Peak oxygen consumption was not different between CAP (5.34 +/- 0.55 mumols.min-1.g-1) and control (5.74 +/- 0.43) groups and required only 56-68% of the oxygen delivered. This implies that rat skeletal muscle can suffer a significant reduction in its electron transport capacity without impairing peak oxygen consumption and muscle performance.(ABSTRACT TRUNCATED AT 250 WORDS)

II. Morphological Adaptations of Human Skeletal Muscle to Chronic Hypoxia*

Muscle structural changes during typical mountaineering expeditions to the Himalayas were assessed by taking muscle biopsies from 14 mountaineers before and after their sojourn at high altitude (greater than 5000 m for over 8 weeks). M. vastus lateralis samples were analyzed morphometrically from electron micrographs. A significant reduction (-10%) of muscle cross-sectional area was found on CT scans of the thigh. Morphologically this loss in muscle mass appeared as a decrease in muscle fiber size mainly due to a loss of myofibrillar proteins. A loss of muscle oxidative capacity was also evident, as indicated by a decrease in the volume of muscle mitochondria (-25%). In contrast, the capillary network was mostly spared from catabolism. It is therefore concluded that oxygen availability to muscle mitochondria after prolonged high-altitude exposure in humans is improved due to an unchanged capillary network, supplying a reduced muscle oxidative capacity.