Multimodality assessment of heart failure with preserved ejection fraction skeletal muscle reveals differences in the machinery of energy fuel metabolism

Abstract

Aims Skeletal muscle (SkM) abnormalities may impact exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF). We sought to quantify differences in SkM oxidative phosphorylation capacity (OxPhos), fibre composition, and the SkM proteome between HFpEF, hypertensive (HTN), and healthy participants. Methods and results Fifty-nine subjects (20 healthy, 19 HTN, and 20 HFpEF) performed a maximal-effort cardiopulmonary exercise test to define peak oxygen consumption (VO 2, peak ), ventilatory threshold (VT), and VO 2 efficiency (ratio of total work performed to O 2 consumed). SkM OxPhos was assessed using Creatine Chemical-Exchange Saturation Transfer (CrCEST, n = 51), which quantifies unphosphorylated Cr, before and after plantar flexion exercise. The half-time of Cr recovery (t 1/2, Cr ) was taken as a metric of in vivo SkM OxPhos. In a subset of subjects (healthy = 13, HTN = 9, and HFpEF = 12), percutaneous biopsy of the vastus lateralis was performed for myofibre typing, mitochondrial morphology, and proteomic and phosphoproteomic analysis. HFpEF subjects demonstrated lower VO 2,peak , VT, and VO 2 efficiency than either control group (all P < 0.05). The t 1/2, Cr was significantly longer in HFpEF (P = 0.005), indicative of impaired SkM OxPhos, and correlated with cycle ergometry exercise parameters. HFpEF SkM contained fewer Type I myofibres (P = 0.003). Proteomic analyses demonstrated (a) reduced levels of proteins related to OxPhos that correlated with exercise capacity and (b) reduced ERK signalling in HFpEF. Conclusions Heart failure with preserved ejection fraction patients demonstrate impaired functional capacity and SkM OxPhos. Reductions in the proportions of Type I myofibres, proteins required for OxPhos, and altered phosphorylation signalling in the SkM may contribute to exercise intolerance in HFpEF.

trans 10, cis 12, but Not cis 9, trans 11 Conjugated Linoleic Acid Isomer Enhances Exercise Endurance by Increasing Oxidative Skeletal Muscle Fiber Type via Toll-like Receptor 4 Signaling in Mice

“…Many studies have shown that mitochondrial metabolism is related to skeletal metabolism and fiber type. Changes in mitochondrial metabolism will lead to changes in skeletal muscle function and thus affect the exercise performance. , Consistent with the previous reports, we observed that t10, c12-CLA effectively promoted endurance capacity by altering muscle fiber type and oxidative metabolism. Besides, it has also been reported that CLA mixture promoted endurance capacity .…”

Isolated knee extensor exercise training improves skeletal muscle vasodilation, blood flow, and functional capacity in patients with HFpEF

“…Previously, a series of investigations identified severe reductions in the leg and forearm vascular conductance during exercise in HFpEF that are not attributable to disease‐related decrements in cardiac or conduit arterial dysfunction (Lee, Barrett‐O'Keefe, Nelson, et al, 2016 ; Ratchford et al, 1985 ; Ratchford et al, 2019 ). These findings are in line with findings of microvascular dysfunction and skeletal muscle structural and oxidative deficiencies in HFpEF (Kitzman et al, 2014 ; Zamani et al, 2021 ). Our results confirm the presence of diminished skeletal muscle vasodilation during exercise in HFpEF patients (Lee, Barrett‐O'Keefe, Nelson, et al, 2016 ; Ratchford et al, 1985 ).…”

“…While blood flow was also improved, IKE training did not restore blood flow fully to the levels measured in healthy controls. This failure to fully normalize blood flow may indicate that some metabolic adaptations, for example, changes in muscle fiber type, capillarity (Kitzman et al, 2014 ; Zamani et al, 2021 ), or mitochondrial function (Molina et al, 2016 ) that determine O 2 demand and therefore blood flow, may be slower to improve in response to 8 weeks of IKE relative to vasodilatory responsiveness. Direct metrics of skeletal muscle structural and biochemical adaptations were not assessed in the current investigation, however, improvements in convective oxygen delivery alone are generally insufficient to improve oxidative capacity (Roca et al, 1992 ).…”

Empagliflozin Preserves Skeletal Muscle Function in a HFpEF Rat Model

“…Our group was one of the first to report reduced mitochondrial respiratory capacity in the skeletal muscle of an animal model of HFpEF (Dahl salt-sensitive rat model) [ 7 ]. These experimental findings were recently supported by a clinical study in HFpEF patients showing impaired oxidative phosphorylation (measured indirect using the Creatine Chemical-Exchange Saturation Transfer (CrCEST) method) and reductions in proteins and complexes involved in energy fuel metabolism [ 44 ]. Impairment in oxidative phosphorylation (RCR value of complex II and respiratory activity of complex IV) was also confirmed in the present study measuring oxygen consumption in saponin-skinned muscle fibers.…”