Bruno Grassi

Oxygen uptake on-kinetics in dog gastrocnemius in situ following activation of pyruvate dehydrogenase by dichloroacetate.

The aim of the present study was to determine whether the activation of the pyruvate dehydrogenase complex (PDC) by dichloroacetate (DCA) is associated with faster O2 uptake (V̇O2) on‐kinetics. V̇O2 on‐kinetics was determined in isolated canine gastrocnemius muscles in situ (n= 6) during the transition from rest to 4 min of electrically stimulated isometric tetanic contractions, corresponding to ∼60–70 % of peak V̇O2. Two conditions were compared: (1) control (saline infusion, C); and (2) DCA infusion (300 mg (kg body mass)−1, 45 min before contraction). Muscle blood flow (Q̇) was measured continuously in the popliteal vein; arterial and popliteal vein O2 contents were measured at rest and at 5–7 s intervals during the transition. Muscle V̇O2 was calculated as Q̇ multiplied by the arteriovenous O2 content difference. Muscle biopsies were taken before and at the end of contraction for determination of muscle metabolite concentrations. DCA activated PDC at rest, as shown by the 9‐fold higher acetylcarnitine concentration in DCA (vs. C; P < 0.0001). Phosphocreatine degradation and muscle lactate accumulation were not significantly different between C and DCA. DCA was associated with significantly less muscle fatigue. Resting and steady‐state V̇O2 values during contraction were not significantly different between C and DCA. The time to reach 63 % of the V̇O2 difference between the resting baseline and the steady‐state V̇O2 values during contraction was 22.3 ± 0.5 s in C and 24.5 ± 1.4 s in DCA (n.s.). In this experimental model, activation of PDC by DCA resulted in a stockpiling of acetyl groups at rest and less muscle fatigue, but it did not affect ‘anaerobic’ energy provision and V̇O2 on‐kinetics.

Regulation of oxygen consumption at exercise onset: is it really controversial?

GRASSI, B. Regulation of oxygen consumption at exercise onset: is it really controversial? Exerc. Sport Sci. Rev., Vol. 29, No. 3, pp 134–138, 2001. The conflicting hypotheses on the limiting factors for skeletal muscle &OV0312;o2 on-kinetics might be reconciled in a unifying scenario. Under “normal” conditions, during transitions to moderate-intensity exercise, the limiting factor appears to be an inertia of oxidative metabolism. During transitions to exercise of higher metabolic intensity, O2 delivery could play a relatively minor but significant role as a limiting factor.

Skeletal muscle VO2 on-kinetics: set by O2 delivery or by O2 utilization? New insights into an old issue.

Recent work conducted by our group has expanded knowledge on some basic issues related to pulmonary and skeletal muscle O2 uptake (VO2) on-kinetics. We demonstrated that, in exercising humans during transitions from unloaded pedaling to loaded pedaling below the ventilatory threshold, alveolar VO2 on-kinetics can be taken as a rather close approximation of skeletal muscle VO2 on-kinetics. Experiments conducted on the isolated in situ dog gastrocnemius preparation have shown that, during transitions from rest to contractions corresponding to approximately 70% of the muscle peak VO2, convective O2 delivery to muscle, intramuscular blood flow (Q) versus VO2 maldistribution, and peripheral O2 diffusion are not limiting factors for skeletal muscle VO2 on-kinetics. The latter, therefore, appears to be mainly determined by an intrinsic inertia of skeletal muscle oxidative metabolism, possibly related to acetyl group availability within mitochondria, to regulatory effects on intracellular respiration related to phosphocreatine splitting, and/or to other still not precisely identified control mechanism(s). Evidence from the literature suggests that the limiting factors for skeletal muscle VO2 on-kinetics may vary according to the intensity of muscular contractions or of exercise.

Skeletal Muscle Fatigue and Decreased Efficiency: Two Sides of the Same Coin?

During high-intensity submaximal exercise, muscle fatigue and decreased efficiency are intertwined closely, and each contributes to exercise intolerance. Fatigue and muscle inefficiency share common mechanisms, for example, decreased “metabolic stability,” muscle metabolite accumulation, decreased free energy of adenosine triphosphate breakdown, limited O2 or substrate availability, increased glycolysis, pH disturbance, increased muscle temperature, reactive oxygen species production, and altered motor unit recruitment patterns.

Impaired oxygen extraction in metabolic myopathies: Detection and quantification by near-infrared spectroscopy

Patients with mitochondrial myopathies (MM) or myophosphorylase deficiency (McArdles disease, McA) show impaired capacity for O2 extraction, low maximal aerobic power, and reduced exercise tolerance. Non‐invasive tools are needed to quantify the metabolic impairment. Six patients with MM, 6 with McA, 25 with symptoms of metabolic myopathy but negative biopsy (patient‐controls, P‐CTRL) and 20 controls (CTRL) underwent an incremental cycloergometric test. Pulmonary O2 uptake (V̇O2) and vastus lateralis oxygenation indices (by near‐infrared spectroscopy, NIRS) were determined. Concentration changes of deoxygenated hemoglobin and myoglobin (Δ[deoxy(Hb + Mb)]) were considered an index of O2 extraction. Δ[deoxy(Hb + Mb)] peak (percent limb ischemia) was lower in MM (25.3 ± 12.0%) and McA (18.7 ± 7.3) than in P‐CTRL (62.4 ± 3.9) and CTRL (71.3 ± 3.9) subjects. V̇O2 peak and Δ[deoxy(Hb + Mb)] peak were linearly related (r2 = 0.83). In these patients, NIRS is a tool to detect and quantify non‐invasively the metabolic impairment, which may be useful in the follow‐up of patients and in the assessment of therapies and interventions. Muscle Nerve, 2006

Comparison of low-frequency electrical myostimulation and conventional aerobic exercise training in patients with chronic heart failure.

Background Physical training is recommended as an efficient therapy in patients with chronic heart failure (CHF). Low-frequency electrical myostimulation (EMS) has recently been suggested as a good alternative to conventional aerobic training. The aim of this study was to compare the effects of EMS and conventional exercise training in patients with moderate to severe CHF. Methods Twenty-four patients with stable CHF (56.7±7.3 years, New York Heart Association grades II and III) underwent 5 weeks of exercise training, 5h a week, using EMS (n=12) or conventional (n=12) training programmes. At baseline and after the training period, patients performed a symptom-limited cardiopulmonary test, a 6-min and a 200-m walk exercises and an evaluation of maximal knee extensor strength. Results Oxygen uptake (VO2) and workload at the end of exercise (peak values) and at ventilatory threshold increased after EMS (P ≤ 0.05) and conventional exercise (P<0.05) training programmes. The slope of the relationship between VO2 and workload was reduced after EMS (P<0.05). The time to recover half of peak VO2 decreased irrespective of the training programme (P<0.001). EMS and conventional exercise training programmes also increased the maximal knee extensor strength (P<0.05), the distance walked in 6 min (P<0.01) and decreased the time elapsed to cover 200 m (P<0.05). These improvements were not statistically different between EMS and conventional exercise. Conclusion In patients with moderate to severe CHF, 5 weeks of EMS and conventional exercise training produce similar improvements to exercise capacity and muscle performance.

Peak anaerobic power in master athletes

SummaryThe age-related decline in maximal physical performance of healthy subjects may be attributed both to the aging process per se and/or to a progressive reduction in physical activity. In two groups of master athletes, power (P) or endurance (E) trained (n = 115; aged 40–78 years), the degree and rate of the age-related deterioration of the maximal instantaneous muscle power (peak power,Wpeak, and the relative contribution ofquantitative (muscle mass) andqualitative factors possibly underlying such deterioration were determined. Two groups of young athletes (n = 20; 17–26 years) and healthy untrained subjects (U,n = 37; 22–67 years) were also tested for comparison. The following two variables were assessed, firstly the lower limb muscle plus bone volume (LMV) by anthropometry, and secondlyWpeak, by means of a standardized vertical jump off both feet, performed on a force platform. The results obtained were that LMV of E and P, as well as of U, was about the same between age 20 and 45 years, whereas at older ages a progressive reduction was observed; the LMV values were higher in P than in E and U. TheWpeak, expressed in W and in W·kg−1 body mass, both in E and P, decreased linearly as a function of age, being at age 75 years about 50% of the value measured at age 20 years (corresponding to a reduction of about 1%year−1); whenWpeak was expressed per kg of LMV, the percentage reduction between athletes aged 20 and 45 years was the same as that observed forWpeak, in W and W·kg−1 body mass, whereas between age 45 and 75 years the difference was almost halved; in all age-groups (with the exception of the oldest)Wpeak was higher in P than in E and in U. It was concluded that at 75 yearsWpeak was reduced, both in absolute units and per kg body mass, to about 50% of the value measured at age 20 years; up to about age 45 years such deterioration was mainly attributable toqualitative factors, whereas after that agequantitative (muscle mass) factors were also involved.

Gas exchange and metabolic transients in heart transplant recipients

In human heart transplant recipients (HTR) an impairment of the cardiac function was expected to reduce peak oxygen consumption and the kinetics of the adjustment of respiratory gas exchange at the onset of rectangular work loads. In nine patients (males, 23-59 yr) 1 to 8 months after cardiac transplantation average peak VO2 (VO2p) was 1.1 L.min-1 +/- 0.3 (SD), i.e. 45% of that of the controls, the corresponding VCO2p value being 1.4 L.min-1 +/- 0.3 (SD). Mean VEp was 62.9 L.min-1 +/- 20.3 (SD), mean HRp was 136 beats.min-1 +/- 11 (SD), i.e. 45 beats.min-1 higher than preexercise values. Mean [Lab]p was 7.7 mM +/- 1.7 (SD), indicating that at the heaviest load the HTR were performing work at or above their maximum aerobic power. During the initial 60-90 sec of the transition from rest to graded rectangular exercise HR did not change from the resting value, increasing thereafter almost linearly with time. The half time (t1/2) of the VE on-response was 112 sec +/- 30 (SD) (controls values: 59 sec +/- 16), that of the VCO2 on- was 95 sec +/- 18 (SD) (58 sec +/- 11), and that of the VO2 on- was 78 sec +/- 24 (SD) (38 sec +/- 6). In spite of the slow kinetics of the VO2 on- response, no massive accumulation of lactate was found in the early phase of exercise. The limitation of the peak exercise in HTR appears to be imposed by a reduced maximal cardiac performance. The slow readjustment of the latter, as expected from the sluggish heart rate response, however, does not impair substantially the work load transients nor reduce the anaerobic threshold.

Effects of a one-year exercise training program in adults over 70 years old: a study with a control group

Background and aims: Exercise training is known to improve exercise tolerance in elderly subjects. Therefore the present study aimed at investigating the effects of one year of combined endurance and resistance training in healthy older people. Methods: After baseline evaluation, subjects were assigned to either the training group (n=24, age 77.2±3.6) or the control group (n=16, age 76.1±4.8). Subjects in the control group did not change anything in their everyday activities, whereas subjects in the training group underwent moderately intensive combined exercise training, 3 hours a week over the course of one year. Breath-by-breath oxygen uptake and heart rate were measured at each workload during the symptom-limited cardiopulmonary exercise test. Performance on the 6-minute (6-MWT) and 200-meter (200-MWT) walk tests was registered and maximal strength was measured on knee extensor and plantar flexor muscles. Results: After training, oxygen uptake was significantly increased, both at the ventilatory threshold (+11.6%, p<0.01) and at the end of exercise (+14.8%, p<0.001). The distance walked in 6 min (+10%, p<0.001), the time required to cover 200 m (−7.3%, p<0.001) and the maximal muscle strength (+15.2% and +17.4% for knee extensors and plantar flexors respectively, p<0.05) also improved after training. All these parameters had not significantly changed in the control group after the one-year period. Conclusions: The results of the present study show that one year of combined exercise training is well-tolerated and improves aerobic capacity, performance on field tests and muscle strength in healthy subjects over 70 years old.

The role of alterations in mitochondrial dynamics and PGC‐1α over‐expression in fast muscle atrophy following hindlimb unloading

Skeletal muscle atrophy occurs as a result of disuse. Although several studies have established that a decrease in protein synthesis and increase in protein degradation lead to muscle atrophy, little is known about the triggers underlying such processes. A growing body of evidence challenges oxidative stress as a trigger of disuse atrophy; furthermore, it is also becoming evident that mitochondrial dysfunction may play a causative role in determining muscle atrophy. Mitochondrial fusion and fission have emerged as important processes that govern mitochondrial function and PGC‐1α may regulate fusion/fission events. Although most studies on mice have focused on the anti‐gravitary slow soleus muscle as it is preferentially affected by disuse atrophy, several fast muscles (including gastrocnemius) go through a significant loss of mass following unloading. Here we found that in fast muscles an early down‐regulation of pro‐fusion proteins, through concomitant AMP‐activated protein kinase (AMPK) activation, can activate catabolic systems, and ultimately cause muscle mass loss in disuse. Elevated muscle PGC‐1α completely preserves muscle mass by preventing the fall in pro‐fusion protein expression, AMPK and catabolic system activation, suggesting that compounds inducing PGC‐1α expression could be useful to treat and prevent muscle atrophy.