Dissociation Between External Power And Muscle Metabolism During Intermittent Bilateral Knee-extensor Exercise Carrie Ferguson, Matthew J. Davies, Alan P. Benson, William E. Bimson, Daniel T. Cannon, Simon Marwood, Graham J. Kemp, Harry B. Rossiter, FACSM. University of Leeds, Leeds, United Kingdom. University of Liverpool, Liverpool, United Kingdom. Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA. Liverpool Hope University, Liverpool, United Kingdom. (Sponsor: Dr Harry Rossiter, FACSM) Email: C.Ferguson@leeds.ac.uk

Key points Heavy‐intensity exercise causes a progressive increase in energy demand that contributes to exercise limitation. This inefficiency arises within the locomotor muscles and is thought to be due to an increase in the ATP cost of power production; however, the responsible mechanism is unresolved. We measured whole‐body O 2 uptake and skeletal muscle ATP turnover by combined pulmonary gas exchange and magnetic resonance spectroscopy during moderate and heavy exercise in humans. Muscle ATP synthesis rate increased throughout constant‐power heavy exercise, but this increase was unrelated to the progression of whole‐body inefficiency. Our data indicate that the increased ATP requirement is not the sole cause of inefficiency during heavy exercise, and other mechanisms, such as increased O 2 cost of ATP resynthesis, may contribute. Abstract During constant‐power high‐intensity exercise, the expected increase in oxygen uptake ( ) is supplemented by a slow component ( ), reflecting reduced work efficiency, predominantly within the locomotor muscles. The intracellular source of inefficiency is postulated to be an increase in the ATP cost of power production (an increase in P/W). To test this hypothesis, we measured intramuscular ATP turnover with 31 P magnetic resonance spectroscopy (MRS) and whole‐body during moderate (MOD) and heavy (HVY) bilateral knee‐extension exercise in healthy participants ( n = 14). Unlocalized 31 P spectra were collected from the quadriceps throughout using a dual‐tuned ( 1 H and 31 P) surface coil with a simple pulse‐and‐acquire sequence. Total ATP turnover rate (ATP tot ) was estimated at exercise cessation from direct measurements of the dynamics of phosphocreatine (PCr) and proton handling. Between 3 and 8 min during MOD, there was no discernable (mean ± SD, 0.06 ± 0.12 l min −1 ) or change in [PCr] (30 ± 8 vs . 32 ± 7 m m ) or ATP tot (24 ± 14 vs . 17 ± 14 m m min −1 ; each P = n.s.). During HVY, the was 0.37 ± 0.16 l min −1 (22 ± 8%), [PCr] decreased (19 ± 7 vs . 18 ± 7 m m , or 12 ± 15%; P < 0.05) and ATP tot increased (38 ± 16 vs . 44 ± 14 m m min −1 , or 26 ± 30%; P < 0.05) between 3 and 8 min. However, the increase in ATP tot (ΔATP tot ) was not correlated with the during HVY ( r 2 = 0.06; P = n.s.). This lack of relationship between ΔATP tot and , together with a steepening of the [PCr]– relationship in HVY, suggests that reduced work efficiency during heavy exercise arises from both contractile (P/W) and mitochondrial sources (the O 2 cost of ATP resynthesis; P/O).

Non-alcoholic fatty liver disease (NAFLD), characterized by lipid deposition within the liver [intrahepatocellular lipid (IHCL)], is associated with insulin resistance and the metabolic syndrome (MS). It has been suggested that impaired skeletal muscle mitochondrial function may contribute to ectopic lipid deposition, and the associated MS, by altering post-prandial energy storage. To test this hypothesis, we performed a cross-sectional study of 17 patients with NAFLD [mean±S.D.; age, 45±11 years; body mass index (BMI), 31.6±3.4 kg/m2] and 18 age- and BMI-matched healthy controls (age, 44±11 years; BMI, 30.5±5.2 kg/m2). We determined body composition by MRI, IHCL and intramyocellular (soleus and tibialis anterior) lipids (IMCLs) by proton magnetic resonance spectroscopy (1H-MRS) and skeletal muscle mitochondrial function by dynamic phosphorus magnetic resonance spectroscopy (31P-MRS) of quadriceps muscle. Although matched for BMI and total adiposity, after statistical adjustment for gender, patients with NAFLD (defined by IHCL ≥ 5.5%) had higher IHCLs (25±16% compared with 2±2%; P<0.0005) and a higher prevalence of the MS (76% compared with 28%) compared with healthy controls. Despite this, the visceral fat/subcutaneous fat ratio, IMCLs and muscle mitochondrial function were similar between the NAFLD and control groups, with no significant difference in the rate constants of post-exercise phosphocreatine (PCr) recovery (1.55±0.4 compared with 1.51±0.4 min-1), a measure of muscle mitochondrial function. In conclusion, impaired muscle mitochondrial function does not seem to underlie ectopic lipid deposition, or the accompanying features of the MS, in patients with NAFLD.

BACKGROUND:In the United Kingdom, patients with locally advanced rectal cancer routinely receive neoadjuvant chemoradiotherapy. However, the effects of this on physical fitness are unclear. This pilot study is aimed to investigate the effect of neoadjuvant chemoradiotherapy on objectively measured in vivo muscle mitochondrial function and whole-body physical fitness.METHODS:We prospectively studied 12 patients with rectal cancer who completed standardized neoadjuvant chemoradiotherapy, recruited from a large tertiary cancer centre, between October 2012 and July 2013. All patients underwent a cardiopulmonary exercise test and a phosphorus magnetic resonance spectroscopy quadriceps muscle exercise-recovery study before and after neoadjuvant chemoradiotherapy. Data were analysed and reported blind to patient identity and clinical course. Primary variables of interest were the two physical fitness measures; oxygen uptake at estimated anaerobic threshold and oxygen uptake at Peak exercise (ml.kg-1.min-1), and the post-exercise phosphocreatine recovery rate constant (min-1), a measure of muscle mitochondrial capacity in vivo.RESULTS:Median age was 67 years (IQR 64-75). Differences (95%CI) in all three primary variables were significantly negative post-NACRT: Oxygen uptake at estimated anaerobic threshold -2.4 ml.kg-1.min-1 (-3.8, -0.9), p = 0.004; Oxygen uptake at Peak -4.0 ml.kg-1.min-1 (-6.8, -1.1), p = 0.011; and post-exercise phosphocreatine recovery rate constant -0.34 min-1 (-0.51, -0.17), p<0.001.CONCLUSION:The significant decrease in both whole-body physical fitness and in vivo muscle mitochondrial function raises the possibility that muscle mitochondrial mechanisms, no doubt multifactorial, may be important in deterioration of physical fitness following neoadjuvant chemoradiotherapy. This may have implications for targeted interventions to improve physical fitness pre-surgery.TRIAL REGISTRATION:Clinicaltrials.gov registration NCT01859442.

In exercising muscle, creatine kinase ensures that mismatch between ATP supply and ATP use results in net phosphocreatine (PCr) splitting. This, inter alia , makes 31 P magnetic resonance spectroscopy a useful tool for studying muscle ‘energy metabolism’ noninvasively in vivo . We combined this with near–infrared spectroscopy (NIRS) to study ATP synthesis and oxygenation in calf muscle of normal subjects and patients with peripheral vascular disease. Experimental and clinical details and basic data have been published elsewhere (G.J. Kemp et al., Journal of Vascular Surgery 34 (2001), 1103–10); we here propose an analysis of interactions between metabolic ‘error signals’ and cellular PO 2 (estimated from NIRS changes, provisionally assumed to reflect deoxymyoglobin). Post–exercise PCr recovery is monoexponential, and the linear relationship between PCr resynthesis rate (= oxidative ATP synthesis) and the perturbation in PCr (conceptually the simplest error signal) is consistent with negative feedback. In patients the inferred ‘mitochondrial capacity’ (= oxidative ATP synthesis at ‘zero’ PCr) is decreased by 53±6%, leading to reduced oxidative ATP contribution in exercise, because of increased deoxygenation. Increased PCr perturbation partially outweighs cellular hypoxia, but as low cellular PO 2 is required for capillary–mitochondrion O 2 diffusion, rate–signal relationships may overstate maximum oxidative ATP synthesis rate.