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 (R2 = 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.

中文翻译：

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患有糖尿病的慢性心力衰竭的特征在于严重的骨骼肌病变。

背景与没有 DM 的 CHF 患者相比，同时患有慢性心力衰竭 (CHF) 和糖尿病 (DM) 的患者表现出更大的运动限制和更差的预后，即使在纠正了心功能不全的情况下也是如此。了解该亚组症状的起源可能有助于开发靶向治疗。因此，我们描述了糖尿病心力衰竭 (D-HF) 患者的骨骼肌表型及其与运动限制的关系。方法 在 CHF 人群中最大的肌肉取样研究之一中，胸大肌活检取自年龄匹配的对照 (n = 25)、DM (n = 10)、CHF (n = 52) 和 D-HF (n = 28) 患者。原位线粒体功能和活性氧，纤维形态，毛细血管，进行基因表达分析，并将其与全身运动能力相关联。结果D-HF患者的线粒体呼吸、含量、耦合效率和内在功能均低于其他组（P < 0.05）。仅在 D-HF 患者中存在独特的线粒体复合物 I 功能障碍 (P < 0.05)，这与运动能力密切相关 (R2 = 0.64; P < 0.001)。D-HF 的线粒体损伤对应于更高水平的线粒体活性氧 (P < 0.05) 和抗氧化酶超氧化物歧化酶 2 (P < 0.05) 和复合物 I 亚基 NDUFS1 (P < 0.05) 的较低基因表达。D-HF 还与严重的纤维萎缩（P < 0.05）和局部纤维毛细血管减少（P < 0.05）有关。结论 D-HF 患者出现特定的骨骼肌病理，其特征是线粒体损伤、纤维萎缩和与运动不耐受有关的毛细血管网络紊乱。这些新的初步数据支持骨骼肌作为治疗 D-HF 患者的潜在治疗靶点。