Non-technical summary We investigated the role of thin fibre muscle afferents in the circulatory response to exercise in humans. The results not only document the importance of continuous afferent feedback from working human skeletal muscle to achieve appropriate haemodynamic and ventilatory responses to exercise but also suggest that the relative contribution of this mechanism is larger than traditionally accepted. AbstractWe investigated the role of skeletal muscle afferent feedback in circulatory control during rhythmic exercise in humans. Nine healthy males performed single leg knee-extensor exercise (15/30/45 watts, 3 min each) under both control conditions (Ctrl) and with lumbar intrathecal fentanyl impairing μ-opioid receptor-sensitive muscle afferents. Cardiac output and femoral blood flow were determined, and femoral arterial/venous blood samples were collected during the final minute of each workload. To rule out cephalad migration of fentanyl to the brainstem, we documented unchanged resting ventilatory responses to different levels of hypercapnia. There were no haemodynamic differences between conditions at rest. However, during exercise cardiac output was ∼20% lower with fentanyl blockade compared to control (P < 0.05), secondary to a 6% and 13% reduction in heart rate and stroke volume, respectively. Throughout exercise mean arterial pressure (MAP) was reduced by 7% (P < 0.01) which is likely to have contributed to the 15% fall in femoral blood flow. However, MAP was not completely responsible for this peripheral haemodynamic change as vascular conductance was also attenuated (∼9%). Evidence of increasing noradrenaline spillover (P = 0.09) implicated an elevation in sympathetic outflow in this response. The attenuated femoral blood flow during exercise with fentanyl was associated with a 17% reduction in leg O 2 delivery (P < 0.01) and a concomitant rise in the arteriovenous O 2 difference (4-9%), but leg O 2 consumption remained 7-13% lower than control (P < 0.05). Our findings reveal an essential contribution of continuous muscle afferent feedback to ensure the appropriate haemodynamic and ultimately metabolic response to rhythmic exercise in humans. Abbreviations FBF, femoral blood flow; HR, heart rate; LVC, leg vascular conductance; MAP, mean arterial pressure; NA, noradrenaline; SV, stroke volume.

Objectives This study sought to elucidate the mechanisms responsible for the benefits of small muscle mass exercise training in patients with chronic heart failure (CHF). Background How central cardiorespiratory and/or peripheral skeletal muscle factors are altered with small muscle mass training in CHF is unknown. Methods We studied muscle structure and oxygen (O2) transport and metabolism at maximal cycle (whole body) and knee-extensor exercise (KE) (small muscle mass) in 6 healthy controls and 6 patients with CHF who then performed 8 weeks of KE training (both legs, separately) and repeated these assessments. Results Pre-training cycling and KE peak leg O2 uptake (VO2peak) were ~17% and ~15% lower, respectively, in the patients compared to controls. Structurally, KE training increased quadriceps muscle capillarity and mitochondrial density by ~21 and ~25%, respectively. Functionally, despite not altering maximal cardiac output, KE training increased maximal O2 delivery (~54%), arterial-venous O2 (a–v O2) difference (~10%), and muscle O2 diffusive conductance (DMO2) (~39%) (assessed during KE), thereby increasing single leg VO2peak by ~53%, to a level exceeding that of the untrained controls. Post-training, during maximal cycling, O2 delivery (~40%), a–v O2 difference (~15%), and DMO2 (~52%) all increased, yielding an increase in VO2peak of ~40%, matching the controls. Conclusions In the face of continued central limitations, clear improvements in muscle structure, peripheral convective and diffusive O2 transport, and subsequently O2 utilization support the efficacy of local skeletal muscle training as a powerful approach to combat exercise intolerance in CHF.

Prior studies have implicated accumulation of ceramide in blood vessels as a basis for vascular dysfunction in diet-induced obesity via a mechanism involving type 2 protein phosphatase (PP2A) dephosphorylation of endothelial nitric oxide synthase (eNOS). The current study sought to elucidate the mechanisms linking ceramide accumulation with PP2A activation and determine whether pharmacological inhibition of PP2A in vivo normalizes obesity-associated vascular dysfunction and limits the severity of hypertension. We show in endothelial cells that ceramide associates with the inhibitor 2 of PP2A (I2PP2A) in the cytosol, which disrupts the association of I2PP2A with PP2A leading to its translocation to the plasma membrane. The increased association between PP2A and eNOS at the plasma membrane promotes dissociation of an Akt-Hsp90-eNOS complex that is required for eNOS phosphorylation and activation. A novel small-molecule inhibitor of PP2A attenuated PP2A activation, prevented disruption of the Akt-Hsp90-eNOS complex in the vasculature, preserved arterial function, and maintained normal blood pressure in obese mice. These findings reveal a novel mechanism whereby ceramide initiates PP2A colocalization with eNOS and demonstrate that PP2A activation precipitates vascular dysfunction in diet-induced obesity. Therapeutic strategies targeted to reducing PP2A activation might be beneficial in attenuating vascular complications that exist in the context of type 2 diabetes, obesity, and conditions associated with insulin resistance.