Key pointsr Heavy-intensity exercise causes a progressive increase in energy demand that contributes to exercise limitation.r 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.r 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.r Muscle ATP synthesis rate increased throughout constant-power heavy exercise, but this increase was unrelated to the progression of whole-body inefficiency.r 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 (V O 2 ) is supplemented by aV O 2 slow component (V O 2 sc ), 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-bodyV O 2 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 discernableV O 2 sc (mean ± SD, 0.06 ± 0.12 l min −1 ) or change in [PCr] (30 ± 8 vs. 32 ± 7 mM) or ATP tot (24 ± 14 vs. 17 ± 14 mM min −1 ; each P = n.s.). During HVY, theV O 2 sc was 0.37 ± 0.16 l min −1 (22 ± 8%), [PCr] decreased (19 ± 7 vs. 18 ± 7 mM, or 12 ± 15%; P < 0.05) and ATP tot increased (38 ± 16 vs. 44 ± 14 mM min −1 , or 26 ± 30%; P < 0.05) between 3 and 8 min. However, the increase in ATP tot ( ATP tot ) was not correlated with theV O 2 sc during HVY (r 2 = 0.06; P = n.s.

Heart failure patients with preserved left ventricular ejection fraction (HFpEF) have endothelial dysfunction, but the underlying molecular mechanisms remain unknown. In addition, whether exercise training improves endothelial function in HFpEF is still controversial. The present study therefore aimed to determine the functional and molecular alterations in the endothelium associated with HFpEF, while further assessing the effects of high-intensity interval training (HIT). Female Dahl salt-sensitive rats were randomized for 28 wk into the following groups: 1) control: fed 0.3% NaCl; 2) HFpEF: fed 8% NaCl; and 3) HFpEF + HIT: animals fed 8% NaCl and HIT treadmill exercise. Echocardiography and invasive hemodynamic measurements were used to assess diastolic dysfunction. Endothelial function of the aorta was measured in vitro. Expression of endothelial nitric oxide synthase (eNOS), nicotinamide adenine dinucleotide phosphate-oxidase [NAD(P)H oxidase], and advanced glycation end product (AGE)-modified proteins were quantified by Western blot, and zymography quantified matrix metalloproteinase (MMP) activity. In this model of HFpEF, endothelium-dependent and -independent vasodilation was impaired. However, this was prevented by HIT. In HFpEF protein expression of eNOS was reduced by 47%, but MMP-2 and MMP-9 activity was elevated by 186 and 68%. The expression of AGE-modified proteins was increased by 106%. All of these changes were prevented by HIT. Endothelial function was impaired in this model of HFpEF, which was associated with reduced expression of eNOS, increased MMP activity, and increased AGE-modified proteins. HIT was able to attenuate both these functional and molecular alterations. These findings therefore suggest HFpEF induces endothelial dysfunction, but this is reversible by HIT.

The benefit of regular physical activity and exercise training for the prevention of cardiovascular and metabolic diseases is undisputed. Many molecular mechanisms mediating exercise effects have been deciphered. Personalised exercise prescription can help patients in achieving their individual greatest benefit from an exercise-based cardiovascular rehabilitation programme. Yet, we still struggle to provide truly personalised exercise prescriptions to our patients. In this position paper, we address novel basic and translational research concepts that can help us understand the principles underlying the inter-individual differences in the response to exercise, and identify early on who would most likely benefit from which exercise intervention. This includes hereditary, non-hereditary and sex-specific concepts. Recent insights have helped us to take on a more holistic view, integrating exercise-mediated molecular mechanisms with those influenced by metabolism and immunity. Unfortunately, while the outline is recognisable, many details are still lacking to turn the understanding of a concept into a roadmap ready to be used in clinical routine. This position paper therefore also investigates perspectives on how the advent of ‘big data’ and the use of animal models could help unravel inter-individual responses to exercise parameters and thus influence hypothesis-building for translational research in exercise-based cardiovascular rehabilitation.

The present study provides evidence that endothelial dysfunction occurs in experimental HFpEF and that ET, independent of the studied training modality, reverses endothelial dysfunction and specific molecular alterations. ET may therefore provide an important therapeutic intervention for HFpEF patients.