Background Patients with coexistent chronic heart failure (CHF) and diabetes mellitus (DM) demonstrate greater exercise limitation and worse prognosis compared with CHF patients without DM, even when corrected for cardiac dysfunction. Understanding the origins of symptoms in this subgroup may facilitate development of targeted treatments. We therefore characterized the skeletal muscle phenotype and its relationship to exercise limitation in patients with diabetic heart failure (D-HF). Methods In one of the largest muscle sampling studies in a CHF population, pectoralis major biopsies were taken from age-matched controls (n = 25), DM (n = 10), CHF (n = 52), and D-HF (n = 28) patients. In situ mitochondrial function and reactive oxygen species, fibre morphology, capillarity, and gene expression analyses were performed and correlated to whole-body exercise capacity. Results Mitochondrial respiration, content, coupling efficiency, and intrinsic function were lower in D-HF patients compared with other groups (P < 0.05). A unique mitochondrial complex I dysfunction was present in D-HF patients only (P < 0.05), which strongly correlated to exercise capacity (R 2 = 0.64; P < 0.001). Mitochondrial impairments in D-HF corresponded to higher levels of mitochondrial reactive oxygen species (P < 0.05) and lower gene expression of anti-oxidative enzyme superoxide dismutase 2 (P < 0.05) and complex I subunit NDUFS1 (P < 0.05). D-HF was also associated with severe fibre atrophy (P < 0.05) and reduced local fibre capillarity (P < 0.05).Conclusions Patients with D-HF develop a specific skeletal muscle pathology, characterized by mitochondrial impairments, fibre atrophy, and derangements in the capillary network that are linked to exercise intolerance. These novel preliminary data support skeletal muscle as a potential therapeutic target for treating patients with D-HF.

Heart failure is characterised by limb and respiratory muscle impairments that limit functional capacity and quality of life. However, compared with heart failure with reduced ejection fraction (HFrEF), skeletal muscle alterations induced by heart failure with preserved ejection fraction (HFpEF) remain poorly explored. r Here we report that obese-HFpEF induces multiple skeletal muscle alterations in the rat hindlimb, including impaired muscle mechanics related to shortening velocity, fibre atrophy, capillary loss, and an impaired blood flow response to contractions that implies a perfusive oxygen delivery limitation. r We also demonstrate that obese-HFpEF is characterised by diaphragmatic alterations similar to those caused by denervation-atrophy in Type IIb/IIx (fast/glycolytic) fibres and hypertrophy in Type I (slow/oxidative) fibres. r These findings extend current knowledge in HFpEF skeletal muscle physiology, potentially underlying exercise intolerance, which may facilitate future therapeutic approaches.

The present study aimed to evaluate the effectiveness of an amaranth-based beverage (CHO-P) on cycling performance and hydration status, despite containing a total caloric content higher than that of a commercial sports beverage (CHO-P: 52.48 kcal per 100 mL vs CHO: 24 kcal per 100 mL). In a randomized, crossover design, six cyclists performed two exercise tests separated by seven days. Each test comprised two time-trials (32.20 km and 5 km) separated by 10 min of rest. Participants consumed either an amaranth-based beverage (CHO-P; 10% and 1.5% concentrations) or a commercial sports beverage (CHO; 6%). Changes in hematocrit and body mass, ratings of perceived exertion, and average power were assessed throughout both tests. 32.2-km time-trial performance was enhanced with CHO-P compared to CHO (54.3 ± 4.1 min vs 55.6 ± 4.8 min; p<0.05). However, no other variablemeasured in this study was significantly different between beverage types. Further laboratory based research should be performed to further explore the ergogenic potential of amaranth supplementation during endurance exercise.

Funding Acknowledgements Type of funding sources: None. Background Muscle wasting is common in patients with diabetes mellitus (DM) and chronic heart failure (HF), which exacerbates cachexia and poor quality of life. However, a gap in clinical translation remains as the mechanisms underlying muscle wasting in DM and HF remain poorly validated, with most evidence assumed from experimental small-animal models. Purpose Validate if markers of muscle wasting (e.g., autophagy, proteolysis, myogenesis) were correlated to muscle phenotype and clinical indices in humans with DM and HF. Method Male patients with DM (n=4), HF (n=4; NYHA=2), DMHF (n=7; NYHA=2) were included. DM was classified as a HbA1c level ≥48mmol/mol and HF classified as a left ventricular ejection fraction (LVEF) ≤40%, with patients on optimised medication. Muscle biopsies of pectoralis major were excised during routine pacemaker surgery and frozen at -80°C for both histological and gene expression analysis. Muscle samples were sectioned, stained, and imaged for fibre cross-sectional area and fibre type. RT-PCR gene expression was conducted for markers of muscle regeneration (myod, myogenin), protein degradation (myostatin and autophagy-related LC3B, ATG7, CTSL), and anabolic signalling (IGF-1). Statistical analysis included ANOVAs and correlation analysis to identify relationships between variables. Values of p&lt;0.05 were accepted as significant. Results Groups (DM, HF, DMHF) were not different (P&gt;0.05) in relation to age (79±9, 72±8, 72±10 years) or BMI (24.5±3.6, 28.5±4.2, 29.5±6.0) respectively. Fibre size or fibre type were not different (P&gt;0.05) between groups. In line with this, gene expression for markers of myogenesis and anabolism as well as myostatin were not different (P&gt;0.05) between groups, but a trend in downregulation of the proteolytic autophagy-related genes (LC3B, ATG7, CTSL) in DMHF vs DM or HF was found on average by 21, 36, and 30% respectively. Autophagy-related genes LC3B, ATG7, CTSL were positively correlated (P&lt;0.05) to type IIa fibre numerical density (R=0.82, 0.86, 0.89) and LVEF (R=0.85, 0.92, 0.83), respectively. Conclusion Our findings indicate that gene expression of autophagy could represent a robust marker of muscle wasting and cardiac dysfunction in humans with DM and HF. Muscle biopsies from patients with DM and HF identified the proteolytic system of autophagy, important for cellular homeostasis, may be inhibited and this was correlated to fibre phenotype and LVEF. However, the process of muscle wasting in DM and HF within the clinical setting may not necessarily reflect those reported in animal models given various other markers were not changed.