Moderate-intensity endurance exercise prevents short-term starvation-induced intramyocellular lipid accumulation but not insulin resistance.

Exercise has the potential to alleviate the resistance to insulin-mediated glucose uptake precipitated by elevated circulating free fatty acids (FFAs) in conditions such as obesity, lipid infusion, and starvation. In this study, 6 lean healthy men underwent two 3-day periods of starvation with either no exercise or daily endurance exercise (80 min d(-1) at 50% maximal rate of oxygen consumption) and a 3-day mixed diet without exercise. Insulin sensitivity was determined by intravenous glucose tolerance test, and intramyocellular lipid (IMCL) concentration was measured by (1)H magnetic resonance spectroscopy. In both starvation conditions, fasting plasma FFAs were significantly elevated, whereas plasma glucose and whole-body insulin sensitivity were significantly reduced. Vastus lateralis IMCL to water ratio was significantly elevated after starvation without exercise compared with that after starvation with exercise or that after mixed diet. Intramyocellular lipid to water ratio was not different between starvation with exercise and mixed diet. In healthy lean men, exercise during starvation prevents the accumulation of IMCL yet does not affect the starvation-induced changes in FFAs and insulin sensitivity. Unlike during lipid infusion or obesity-induced insulin resistance, exercise cannot overcome the reduction in insulin action caused by starvation. We propose that carbohydrate availability is a key modulator of the combined effects of exercise and circulating FFAs on insulin sensitivity.

Effects of eccentric exercise-induced muscle damage on intramyocellular lipid concentration and high energy phosphates.

Eccentric exercise is known to cause changes to the ultrastructure of skeletal muscle and, in turn, may alter the ability of the muscle to store and utilise intracellular substrates such as intramyocellular lipid (IMCL). The purpose of this study was to test the hypothesis that exercise-induced muscle damage (EIMD) results in IMCL accumulation. Six males (31 ± 6 years; mean ± SD, and 72.3 ± 9.7 kg body mass) performed 300 unilateral, maximal, isokinetic, eccentric contractions (Ecc) (30° s(-1)) of the quadriceps on an isokinetic dynamometer, followed immediately by an equal amount of work by the contralateral leg but with concentric action (Con). Phosphate compounds and IMCL content of the vastus lateralis of both legs were measured using (31)P and (1)H magnetic resonance spectroscopy. IMCL content was higher in Ecc than Con 24 h post but the reverse was evident 48 h post-exercise (P = 0.046). A significant time × trial interaction for resting [P(i)] (P = 0.045), showed increases in Ecc across time but no change in Con. A significant main effect of trial (P = 0.002) was apparent indicating the Ecc leg had marked metabolic dysfunction. The P(i)/PCr ratio showed a significant effect of trial (P = 0.001) with an increase evident in Ecc leg, primarily due to increases in [P(i)]. The present study highlights changes in IMCL content of skeletal muscle following EIMD.

Low-carbohydrate diet does not affect intramyocellular lipid concentration or insulin sensitivity in lean, physically fit men when protein intake is elevated.

It has been speculated that dietary carbohydrate restriction is solely responsibly for mobilization of endogenous lipid stores, elevation of plasma free fatty acid (FFA) concentration, and an associated reduction in insulin sensitivity seen in starvation and low-carbohydrate diets. In 6 healthy men, dietary carbohydrate was eliminated but gluconeogenic substrate supply was maintained by 3 days of very low-carbohydrate/high-protein (HPLC) diet. Results were compared with 3-day starvation and 3-day mixed-carbohydrate diet. Intramyocellular lipid (IMCL) concentration was measured by ¹H magnetic resonance spectroscopy, and insulin sensitivity was determined by intravenous glucose tolerance test. Fasting plasma glucose was significantly reduced ([starvation] 3.5 ± 0.3 vs [HPLC] 4.2 ± 0.4 and [mixed] 4.5 ± 0.3 mmol L⁻¹, P < .01), and IMCL to water ratio (25.6 ± 5.9 vs 13.6 ± 6.1 and 13.6 ± 3.3 × 10⁻³, P < .01) and fasting FFA (1179 ± 294 vs 387 ± 232 and 378 ± 120 µmol L⁻¹, P < .05) were significantly elevated after starvation but were unchanged after HPLC. Minimal model insulin sensitivity was reduced after starvation (5.7 ± 1.5 vs 14.5 ± 4.8 and 16.5 ± 6.8 L min⁻¹ mU⁻¹, P < .05). Plasma glucose, plasma FFAs, IMCLs, and insulin sensitivity are maintained when an HPLC diet is consumed, despite other forms of carbohydrate deprivation producing marked changes in these measures. We conclude that dietary carbohydrate restriction does not cause circulating FFA to become elevated. However, it remains possible that circulating carbohydrate status has an important influence on plasma FFA and therefore insulin sensitivity in healthy people.

Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without weight loss.

UNLABELLED: Weight loss remains the most common therapy advocated for reducing hepatic lipid in obesity and nonalcoholic fatty liver disease. Yet, reduction of body weight by lifestyle intervention is often modest, and thus, therapies which effectively modulate the burden of fatty liver but are not contingent upon weight loss are of the highest practical significance. However, the effect of aerobic exercise on liver fat independent of weight loss has not been clarified. We assessed the effect of aerobic exercise training on hepatic, blood, abdominal and muscle lipids in 19 sedentary obese men and women using magnetic resonance imaging and proton magnetic resonance spectroscopy ((1)H-MRS). Four weeks of aerobic cycling exercise, in accordance with current physical activity guidelines, significantly reduced visceral adipose tissue volume by 12% (P < 0.01) and hepatic triglyceride concentration by 21% (P < 0.05). This was associated with a significant (14%) reduction in plasma free fatty acids (P < 0.05). Exercise training did not alter body weight, vastus lateralis intramyocellular triglyceride concentration, abdominal subcutaneous adipose tissue volume, (1)H-MRS-measured hepatic lipid saturation, or HOMA-IR (homeostasis model assessment of insulin resistance; P > 0.05). CONCLUSION: These data provide the first direct experimental evidence demonstrating that regular aerobic exercise reduces hepatic lipids in obesity even in the absence of body weight reduction. Physical activity should be strongly promoted for the management of fatty liver, the benefits of which are not exclusively contingent upon weight loss.

Dynamic changes in brain bioenergetics during obstructive sleep apnea.

Repetitive collapse of the upper airway during obstructive sleep apnea/hypopnea (OSA) exposes the brain of sufferers to frequent, transient, hypoxic episodes. The loss of cerebrovascular reactivity in sleep, and particularly in OSA, means that physiologic compensatory mechanisms may not ensure adequate brain oxygen levels. This (31)P magnetic resonance spectroscopy study, of 13 males with severe, untreated OSA undertaken after overnight sleep deprivation, represents the first, seconds time-scale analysis of human brain bioenergetics during transient hypoxia and demonstrates that a moderate degree of oxygen desaturation during sleep has significant effects on brain bioenergetic status. Oxygen desaturation >10% of sleeping baseline resulted in decreases in brain adenosine triphosphate levels (P<0.01), and increases in inorganic phosphate (P<0.0001) with no concomitant changes in phosphocreatine or brain pH. This indicates that the mechanism of adenosine triphosphate depletion in these patients is different to that observed in normoxic, awake working brain. These data show that the buffering capacity of phosphocreatine and the creatine kinase system is not active in mild transient hypoxia and that cerebrovascular compensatory mechanisms are not adequate to prevent decrements in brain high-energy phosphates in OSA. Transient hypoxia experienced during sleep may impair brain function more than previously thought.

Noninvasive assessment of hepatic lipid composition: Advancing understanding and management of fatty liver disorders.

UNLABELLED: Nonalcoholic fatty liver is frequently observed in obese individuals, yet the factors that predict its development and progression to liver disease are poorly understood. We proposed that proton magnetic resonance spectroscopy ((1)H-MRS) might allow noninvasive assessment of hepatic lipid composition. Lipid saturation (SI) and polyunsaturation (PUI) indices measured by (1)H-MRS were in agreement with those expected in oils of known composition. Hepatic triglyceride concentration (HTGC) and composition were then measured in healthy lean (LEAN) men, obese men with normal HTGC (OB), and obese men with hepatic steatosis (OB+HS). The effect of marked changes in dietary fat consumption on hepatic lipids were also compared in lean men after 67 hours of a normal mixed (NM) diet versus a low-carbohydrate, high-saturated-fat (LCHF) diet. SI was significantly higher in OB+HS (0.970 +/- 0.004) and OB (0.944 +/- 0.008) versus LEAN (0.818 +/- 0.025) (P < 0.01 for both). PUI was significantly lower in OB+HS (0.003 +/- 0.001) and OB (0.022 +/- 0.005) versus LEAN (0.120 +/- 0.021) (P < 0.01), and significantly lower in OB+HS versus OB (P < 0.05). LCHF diet did not alter HTGC, SI, or PUI (P > 0.05). The (1)H-MRS method provides for rapid, qualitative assessment of lipid composition. Application of this technique in the liver produces results that are consistent with biopsy-based approaches demonstrating that relative hepatic lipid saturation increases and polyunsaturation decreases with obesity. Obesity-related hepatic steatosis is characterized by further depletion of polyunsaturated hepatic lipids. CONCLUSION: This readily available and noninvasive approach should promote further study into interactions between hepatic and whole-body lipid metabolism and help to elucidate the pathogenesis of disorders characterized by lipid accumulation within the liver.

Effect of short-term starvation versus high-fat diet on intramyocellular triglyceride accumulation and insulin resistance in physically fit men.

It is currently believed that intramyocellular triglyceride (IMTG) accumulation and insulin resistance are a consequence of dietary fat ingestion and/or the elevated circulating lipid levels associated with chronic fat surplus. The purpose of this study was to compare the effect of short-term starvation versus low-carbohydrate (CHO)/high-fat diet on IMTG accumulation and the development of insulin resistance in physically fit men. Intramyocellular triglyceride content, measured as intramyocellular lipid (IMCL) by proton magnetic resonance spectroscopy (1H-MRS), and glucose tolerance/insulin sensitivity, assessed by frequently sampled intravenous glucose tolerance test (IVGTT), were determined after 67 h of: (a) water-only starvation (S); and (b) very low-CHO/high-fat diet (LC). These diets had in common significant restriction of CHO availability but large differences in fat content. All results were compared with those measured after a mixed CHO diet (C). Dietary interventions were administered by cross-over design. The level of dietary-induced IMTG accumulation (P = 0.46), insulin resistance (P = 0.27) and glucose intolerance (P = 0.29) was not different between S and LC treatments. Intramyocellular triglyceride content and insulin sensitivity were negatively correlated (r = -0.63, P < 0.01). Therefore, whilst insulin resistance may be due to fat accumulation at a cellular level, in the integrated human organism this outcome is not exclusively a function of dietary fat intake. The comparable level of IMTG accumulation and insulin resistance following S and LC may suggest that these metabolic perturbations are largely a consequence of the increased lipolytic response associated with CHO restriction.

Exercise capacity and quadriceps muscle metabolism following training in subjects with COPD.

The aim of the study was to determine whether 16 sessions of exercise training, completed twice weekly, alters exercise capacity, quadriceps muscle metabolism, cross-sectional area (CSA) and strength in subjects with chronic obstructive pulmonary disease (COPD). We studied (a) 10 COPD subjects (mean age+/-sem = 71+/-2 years; FEV1 = 0.99+/-0.1 L) before and after 16 sessions of exercise training, and (b) 10 healthy subjects (age = 68+/-3 years). The COPD subjects underwent an incremental peak exercise test using a cycle ergometer and a 6-min walk test: both improved following exercise training (P < 0.05). Magnetic resonance spectroscopy measurements, in quadriceps muscle, of post-exercise phosphocreatinine (PCr) recovery kinetics were used to assess mitochondrial function in vivo: in the COPD subjects pre-training this was 19+/-8% lower than in healthy subjects (P = 0.03), but a 38+/-12% increase was seen in the COPD subjects following training (P = 0.003). Magnetic resonance imaging was used to assess quadriceps CSA: after training in the COPD subjects this showed a 7+/-2% increase (P = 0.03). Quadriceps strength, measured by the best of five maximum voluntary contractions, also showed a 32+/-11% increase in the COPD subjects (P = 0.007). Sixteen sessions of exercise training, performed twice weekly, increased exercise capacity as well as quadriceps mitochondrial capacity, CSA and strength in the subjects with COPD.

Aerobic exercise and muscle metabolism in patients with mitochondrial myopathy.

Exercise therapy improves mitochondrial function in patients with mitochondrial myopathy (MM). We undertook this study to determine the metabolic abnormalities that are improved by exercise therapy. This study identified metabolic pathology using (31)P-magnetic resonance spectroscopy and magnetic resonance imaging (MRI) in a group of patients with MM compared to a control group matched for age, gender, and physical activity. We also observed the effect of exercise therapy for 12 weeks on muscle metabolism and physical function in the MM group. During muscle activity, there was impaired responsiveness of the mitochondria to changes in cytosolic adenosine diphosphate concentration, increased dependence on anaerobic energy pathways, and an adaptive increase in proton efflux in patients with MM. Following exercise therapy, mitochondrial function and muscle mass improved without any change in proton efflux rate. These metabolic findings were accompanied by improvements in functional ability. We conclude that there are significant metabolic differences between patients with MM and a control population, independent of age, gender, and physical activity. Exercise therapy can assist in improving mitochondrial function in MM patients.

Muscle function and resting energy expenditure in female athletes with cystic fibrosis.

The pathophysiology of impaired exercise tolerance in patients with cystic fibrosis (CF) is not completely understood. The objective of this study was to compare exercise ability (at clinical and cellular levels) and resting energy expenditure in female athletes with CF compared with matched control subjects. Sixteen subjects and matched control subjects participated in the study. The girls with CF not only had a significantly greater resting energy expenditure (7.6% higher; p<0.05), their habitual daily activity was also significantly greater than that of control subjects (15% greater; p<0.01). Peak aerobic capacity was similar in both groups. However, peak anaerobic power was 20% less (p<0.05) in girls with CF. The 31P magnetic resonance spectroscopy studies demonstrated that there were no differences between the groups at rest, but at 25% total work output the girls with CF were less acidotic (CF, pH 6.99 [0.06]; control subjects, 6.90 [0.05]) and had a significantly lower inorganic phosphorus-to-phosphocreatine ratio (CF, 0.34 [0.07]; control subjects, 0.41 [0.08]). These differences continued to increase to maximal exercise. This study demonstrates that in spite of normal lung function and good nutritional status, females athletes with CF still had significant deficiencies in some measures of fitness and muscle metabolism compared with healthy athletes.

Cervical ependymoma presenting with brainstem and cerebellar signs: case report.

This case report demonstrates cervical spinal cord pathology which presented with brainstem and cerebellar signs consequent to the peritumoural oedema that extended rostrally to the pontomedullary junction. A Medline search of the literature back to 1960 failed to produce any previous report of a cervical ependymoma presenting with brainstem and cerebellar signs purely consequent to oedema. This case highlights the need to look further afield when presented with the scenario of clinical features of a brainstem lesion with only oedema apparent on cranial imaging. It indicates the need to include cervical imaging well below the foramen magnum in these circumstances.