Divergent skeletal muscle mitochondrial phenotype between male and female patients with chronic heart failure

Abstract

Background Previous studies in heart failure with reduced ejection fraction (HFrEF) suggest that skeletal muscle mitochondrial impairments are associated with exercise intolerance in men. However, the nature of this relationship in female patients remains to be elucidated. This study aimed to determine the relationship between skeletal muscle mitochondrial impairments and exercise intolerance in male and female patients with HFrEF. Methods Mitochondrial respiration, enzyme activity, and gene expression were examined in pectoralis major biopsies from age‐matched male (n = 45) and female (n = 11) patients with HFrEF and healthy‐matched male (n = 24) and female (n = 11) controls. Mitochondrial variables were compared between sex and related to peak exercise capacity. Results Compared with sex‐matched controls, complex I mitochondrial oxygen flux was 17% (P = 0.030) and 29% (P = 0.013) lower in male and female patients with HFrEF, respectively, which correlated to exercise capacity (r = 0.71; P > 0.0001). Female HFrEF patients had a 32% (P = 0.023) lower mitochondrial content compared with controls. However, after adjusting for mitochondrial content, male patients demonstrated lower complex I function by 15% (P = 0.030). Expression of key mitochondrial genes regulating organelle dynamics and maintenance (i.e. optic atrophy 1, peroxisome proliferator‐activated receptor γ coactivator‐1α, NADH:ubiquinone oxidoreductase core subunit S1/S3, and superoxide dismutase 2) were selectively lower in female HFrEF patients. Conclusions These data provide novel evidence that HFrEF induces divergent sex‐specific mitochondrial phenotypes in skeletal muscle that predispose towards exercise intolerance, impacting mitochondrial ‘quantity' in female patients and mitochondrial ‘quality' in male patients. Therapeutic strategies to improve exercise tolerance in HFrEF should consider targeting sex‐specific mitochondrial abnormalities in skeletal muscle.

Chronic heart failure with diabetes mellitus is characterized by a severe skeletal muscle pathology

“…There were no complications or adverse events with this procedure. One piece of muscle sample was immediately placed in 1 mL of ice‐cold specialized preservation solution (BIOPS) for assessment of mitochondrial respiration, while two other portions were divided and rapidly frozen for subsequent histology and molecular analysis.…”

“…Mitochondrial respiration was assessed in situ from saponin‐permeabilized skeletal muscle fibres using high‐resolution respirometry (Oxygraph‐2K; Oroboros Instruments, Innsbruck, Austria) . Briefly, (i) complex I leak respiration was determined by addition of glutamate (10 mM), malate (0.5 mM), and pyruvate (5 mM) (i.e.…”

Senescence in Post-Mitotic Cells: A Driver of Aging?

“…Mitochondrial activity in skeletal muscles has long been known to correlate with exercise capacity ( 39 ), with a recent observation showing that especially with respect to complex I ( 43 ), suggesting mitochondrial function is critical for skeletal muscle function. Mitochondrial content has widely been observed to decrease with age in skeletal muscles ( 58 , 78 , 97 ).…”

Skeletal muscle atrophy in heart failure with diabetes: from molecular mechanisms to clinical evidence

“…It is well established that both patients with HF or DM develop mitochondrial dysfunction, which include for example a lower respiratory function and content. 25,[100][101][102] In patients with HFDM, mitochondrial content has been estimated to be lower by 25%, while mitochondrial dysfunction assessed in situ using high-resolution respirometry showed impairments specific to complex I both absolute and when normalized to mitochondrial content, as assessed in the pectoralis major when compared with patients with HF or DM. 25 This finding is important, as it suggests a complex I-specific impairment related to both quality and quantity in patients with HFDM but not HF or DM, and importantly, this was correlated to whole-body measures of exercise intolerance.…”

“…Recent studies have revealed a large, novel, and poorly characterized clinical population of patients with coexistent HF and DM (i.e. HFDM) 16,25–31 . However, our clinical understanding remains limited due to it being unclear whether DM is causal or an associative comorbidity in HF 32 .…”