Unique Transcriptome Signature Distinguishes Patients With Heart Failure With Myopathy

Abstract

Background People with chronic heart failure (CHF) experience severe skeletal muscle dysfunction, characterized by mitochondrial abnormalities, which exacerbates the primary symptom of exercise intolerance. However, the molecular triggers and characteristics underlying mitochondrial abnormalities caused by CHF remain poorly understood. Methods and Results We recruited 28 patients with CHF caused by reduced ejection fraction and 9 controls. We simultaneously biopsied skeletal muscle from the pectoralis major in the upper limb and from the vastus lateralis in the lower limb. We phenotyped mitochondrial function in permeabilized myofibers from both sites and followed this by complete RNA sequencing to identify novel molecular abnormalities in CHF skeletal muscle. Patients with CHF presented with upper and lower limb skeletal muscle impairments to mitochondrial function that were of a similar deficit and indicative of a myopathy. Mitochondrial abnormalities were strongly correlated to symptoms. Further RNA sequencing revealed a unique transcriptome signature in CHF skeletal muscle characterized by a novel triad of differentially expressed genes related to deficits in energy metabolism including adenosine monophosphate deaminase 3, pyridine nucleotide‐disulphide oxidoreductase domain 2, and lactate dehydrogenase C. Conclusions Our data suggest an upper and lower limb metabolic myopathy that is characterized by a unique transcriptome signature in skeletal muscle of humans with CHF.

Quantifying the relationship and contribution of mitochondrial respiration to systemic exercise limitation in heart failure

“…Here we uniquely developed this line of enquiry by examining the contribution of dynamic mitochondrial respiration across complexes I, II, and IV and ETS in skeletal muscle to prognostic measures of exercise limitation in patients with HFrEF. Recent detailed assessments of mitochondrial respiration in situ have confirmed oxygen flux is lower in patients with HFrEF 30–32 . Impairments to mitochondrial content rather than intrinsic function have been suggested to play the dominant role, with complexe I and IV dysfunction being closely correlated to V̇O 2peak 30–32 .…”

“…We approached consecutive patients with stable signs and symptoms of chronic heart failure (>3 months receiving medical therapy) that were untrained but ambulatory, and presented with a LVEF <50% measured by two‐dimensional echocardiography by Simpson's biplane following current guidelines 33 who were listed for a cardiac implantable electronic device at Leeds Teaching Hospitals NHS Trust, as described in full details elsewhere 30 . Participants were indicated for device therapy with either a pacemaker, implantable cardioverter defibrillator, or cardiac resynchronization therapy device according to current indications 33 .…”

“…The patients included in this study are a subset of those on whom we have previously published other outcomes. [30][31][32] Cardiopulmonary exercise test Cardiopulmonary exercise testing data for patients were obtained from a peak symptom-limited CPET conducted as part of routine clinical care, continued to volitional intolerance on a cycle ergometer for determination of V O 2peak , V O 2LT , peak circulatory power (CircP peak ), and peak oxygen (O 2 ) pulse, RER peak , and V E/V CO 2LT . After a 5-min warm-up at 10 W, the patients started cycling at 20 W and workload was progressively increased by 5 W min À1 until the patients reached volitional intolerance.…”

“…disuse, detraining, or arthritis). 30 Furthermore, muscle mass of the pectoralis major is also a powerful predictor of prognosis in HFrEF 39 and in relation to daily activities, the upper limbs typically perform various tasks (e.g. house chores and gardening) that would pose exercise limitations impacting patient quality of life.…”

“…Mitochondrial respiration was measured in situ from saponin-permeabilized skeletal muscle fibres using high-resolution respirometry (Oxygraph-2K; Oroboros Instruments, Innsbruck, Austria) as previously described elsewhere. [30][31][32] Briefly, the following steps were performed including (i) Complex I leak respiration was determined by addition of glutamate (10 mM), malate (0.5 mM), and pyruvate (5 mM) (i.e. a measure of proton leak under nonphosphorylating conditions); (ii) adenosine diphosphate (2.5 mM) was added to stimulate oxidative phosphorylation through Complex I (OXPHOS P I ); (iii) outer mitochondrial membrane integrity was determined by addition of 10 μM cytochrome c; (iv) succinate at 10 mM to stimulate Complex I + II (OXPHOS P I + II ); (v) 0.5 μM titrations of FCCP to achieve maximal uncoupled respiration for electron transport system (ETS) capacity; (vi) Complex I inhibitor rotenone at 0.25 μM for ETS-supported Complex II respiration (C II ); (vii) 2.5 μM antimycin A as a Complex III inhibitor for residual oxygen consumption (ROX) to calculate non-mitochondrial (background) respiration, which was subtracted from all values.…”