Heart failure (HF) is a final common outcome for many cardiovascular diseases and remains a global health challenge. Despite progress in treatment options, HF incidence and mortality rates remain high. At its core, HF reflects the heart’s inability to maintain energy supply and demand, a failure of the complex metabolism that powers continuous heartbeats across a lifetime.
The heart consumes massive amounts of adenosine triphosphate (ATP) daily but holds minimal reserves. To meet demand, it flexibly shifts between energy sources: mainly fatty acids, glucose, ketones, and branched-chain amino acids (BCAAs). Any disruption in this finely balanced system can trigger functional decline, setting the stage for HF. Energy metabolism disorders are now recognized as early drivers of HF, often preceding structural heart damage.
While medications have focused on easing symptoms and slowing disease, researchers increasingly point to exercise as a promising, low-cost intervention that addresses the underlying metabolic dysfunction. Yet the precise ways exercise reshapes myocardial metabolism have remained partly unclear—until now.
How the Healthy Heart Fuels Itself
Under normal conditions, the heart relies mainly on fatty acid oxidation (60–70% of ATP), with glucose metabolism supplying about 10–30%, and smaller contributions from ketones and amino acids.
Fatty acids (FAs) are absorbed through transporters like CD36, processed into acetyl-CoA, and funneled into the tricarboxylic acid (TCA) cycle to produce ATP. Simultaneously, glucose is taken up primarily via GLUT4 transporters and enters glycolysis. The competition between FA and glucose metabolism, known as the Randle cycle, allows the heart to dynamically shift according to substrate availability and demand.
Ketones and BCAAs also serve as alternative fuels. Although BCAAs contribute less than 2% to ATP production, they influence other critical cellular pathways, including those regulating growth and insulin sensitivity.
What Goes Wrong in Heart Failure
HF disrupts the heart’s energy supply. As HF progresses, fatty acid oxidation declines, often due to impaired signaling through regulators like PPAR-α and PGC-1α. Simultaneously, glucose metabolism increases as compensation but often remains inefficient, leading to energy shortfalls.
An imbalance develops: reduced FA use, incomplete glucose oxidation, and an accumulation of harmful lipid intermediates such as palmitic acid. These changes contribute to mitochondrial dysfunction, oxidative stress, insulin resistance, and eventual cardiac remodeling.
Interestingly, ketone body metabolism becomes more prominent in HF. The failing heart increases ketone uptake and utilization, offering an emergency energy source. However, while moderate β-hydroxybutyrate (βOHB) supplementation shows benefits, excess ketone accumulation might worsen cardiac dysfunction in the long term.
Elevated BCAA levels have been linked to poor cardiovascular outcomes. Impaired BCAA breakdown can exacerbate mitochondrial dysfunction, oxidative stress, and metabolic disturbances.
Exercise: Rebalancing the Heart’s Energy
Exercise can dramatically reshape myocardial metabolism. As the authors describe, “Exercise stimulates catecholamine-driven fat metabolism, elevating circulating FFAs approximately 6–10 times above resting levels.” During activity, the heart enhances fatty acid and lactate oxidation, reducing lipid accumulation and lipotoxicity risks.
Endurance exercise, in particular, boosts mitochondrial density and function, increases fatty acid oxidation, and enhances metabolic flexibility. This supports physiological (healthy) cardiac hypertrophy, not pathological remodeling.
However, excessive exercise (prolonged high-intensity effort) can damage heart structures, disrupt mitochondrial balance, and increase oxidative stress. Thus, the right intensity and duration are crucial to maximizing exercise benefits without triggering harm.
Different Exercises, Different Effects
The authors highlight that not all exercise is equal. High-intensity interval training (HIIT), moderate continuous exercise, and resistance training each differently influence heart metabolism.
For example:
- HIIT improved mitochondrial number and enhanced heart contractility in obese individuals.
- Resistance training mainly preserved plasma membrane integrity.
- Combined training improved insulin sensitivity across all exercise types.
Gender differences also emerged: female mice showed greater metabolic flexibility under high-intensity stress compared to males.
Overall, moderate-to-high intensity aerobic exercise seems most effective for improving heart metabolism without triggering negative remodeling.
Exercise Protects Mitochondria
Mitochondria are central to cardiac health, providing energy and regulating cell survival. Exercise activates key mitochondrial pathways, including the SIRT1/PGC-1α/PI3K/Akt signaling cascade, promoting antioxidant defenses, biogenesis, and function.
Additionally, exercise-induced mitochondrial autophagy helps clear damaged mitochondria, preserving healthy networks and improving energy production.
The authors note that HIIT is particularly potent in enhancing mitochondrial structure and function, while even moderate aerobic training can improve mitochondrial quality control over the long term.
Exerkines: The Heart’s Messengers
A growing area of research focuses on exerkines—molecules secreted in response to exercise that mediate systemic benefits.
Key exerkines include:
- FGF21: Protects mitochondrial function, reduces remodeling, and improves cardiac outcomes.
- Irisin: Promotes mitochondrial autophagy, reduces oxidative stress, and improves cardiac resilience.
- BAIBA: A valine-derived molecule that reduces oxidative stress, inflammation, and improves lipid metabolism.
- CCDC80: Suppresses pro-fibrotic pathways and preserves heart structure.
The study suggests that these molecules could potentially be harnessed to mimic exercise benefits, especially for HF patients unable to engage in sufficient physical activity.
Clinical Implications: A New Role for Exercise in HF Care
This review underscores that exercise acts as a metabolic therapy, restoring energy balance in the failing heart. Moderate aerobic exercise, tailored to the individual’s capacity, enhances mitochondrial health, improves substrate use, and protects against harmful remodeling.
However, “defining exercise dosage limits is crucial,” the authors stress. Too little exercise may have minimal benefit; too much may provoke additional cardiac stress.
Ultimately, exercise should be viewed not just as a lifestyle recommendation but as a targeted intervention for restoring myocardial metabolism and slowing HF progression.
Future research should focus on optimizing exercise prescriptions by integrating molecular markers (like mitochondrial function or exerkine levels) alongside traditional measures like echocardiography.
Final Note
The work by Yuanhao Li and colleagues highlights the complex but promising role of exercise in cardiac rehabilitation. By reprogramming metabolism, protecting mitochondria, and engaging systemic signaling pathways, exercise holds the potential to transform the way we manage heart failure—and prevent it before it takes hold.
The translation of the preceding English text in Chinese:
心力衰竭（HF）是许多心血管疾病的最终共同结局，仍然是全球健康领域的一大挑战。尽管治疗手段不断进步，心力衰竭的发病率和死亡率依然居高不下。从本质上看，心力衰竭反映了心脏无法维持能量供需平衡，是终生持续跳动所需复杂代谢过程失效的结果。
心脏每天消耗大量三磷酸腺苷（ATP），但储备极少。为了满足高能量需求，心脏灵活地在不同能源之间切换：主要是脂肪酸、葡萄糖、酮体和支链氨基酸（BCAA）。这种精细平衡一旦被打破，就可能引发功能下降，为心力衰竭奠定基础。能量代谢障碍如今被认为是心力衰竭早期的重要驱动因素，往往在结构性心脏损伤之前就已出现。
虽然药物治疗主要集中在缓解症状和延缓疾病进展，但研究人员越来越关注运动作为一种有前景、低成本、能够直接改善代谢异常的干预手段。不过，运动如何精准重塑心肌代谢，直到最近仍不完全清楚。
健康心脏如何供能
在正常情况下，心脏主要依赖脂肪酸氧化（占ATP供应的60–70%），葡萄糖代谢供应约10–30%，酮体和氨基酸贡献较小。
脂肪酸（FA）通过如CD36等转运蛋白被吸收，转化为乙酰辅酶A（acetyl-CoA），进入三羧酸循环（TCA循环）产生ATP。同时，葡萄糖主要通过GLUT4转运体摄取，进入糖酵解途径。脂肪酸代谢和葡萄糖代谢之间的竞争关系被称为Randle循环，使心脏可以根据底物可用性和需求动态切换能源。
酮体和支链氨基酸也是替代能源。尽管BCAA在ATP产生中贡献不足2%，但它们参与调控细胞生长和胰岛素敏感性等关键途径。
心力衰竭中出现了什么问题
心力衰竭破坏了心脏的能量供应。随着疾病进展，脂肪酸氧化下降，往往是由于PPAR-α和PGC-1α等关键调控信号受损。同时，葡萄糖代谢作为代偿机制增加，但效率低下，导致能量不足。
这种失衡表现为：脂肪酸利用减少、葡萄糖氧化不完全，以及有害脂质中间产物（如棕榈酸）积累。这些变化导致线粒体功能障碍、氧化应激、胰岛素抵抗，并最终引发心脏重塑。
有趣的是，在心力衰竭中，酮体代谢变得更加重要。衰竭的心脏增加了对酮体的摄取和利用，作为一种应急能量来源。适度补充β-羟基丁酸（βOHB）有益，但酮体积累过多可能在长期内加重心脏功能障碍。
此外，BCAA水平升高与心血管不良结局相关。BCAA分解障碍可进一步恶化线粒体功能障碍、氧化应激和代谢紊乱。
运动：重新平衡心脏能量
运动可以显著重塑心肌代谢。作者指出：“运动刺激了儿茶酚胺驱动的脂肪代谢，使游离脂肪酸（FFAs）水平升高至静息水平的6–10倍。”在运动期间，心脏增强了脂肪酸和乳酸的氧化，减少了脂质积累和脂毒性风险。
尤其是耐力运动，能够增加线粒体密度和功能，提升脂肪酸氧化能力，并增强代谢灵活性。这促进了生理性（健康）心肌肥大，而不是病理性重塑。
然而，过度运动（如长时间高强度训练）可能损伤心脏结构，破坏线粒体平衡，增加氧化应激。因此，适当的运动强度和持续时间对最大化运动益处且避免伤害至关重要。
不同运动，不同效应
作者强调，不同形式的运动对心脏代谢的影响不同。高强度间歇训练（HIIT）、中等强度持续运动和阻力训练各有特点。
例如：
-
HIIT能增加线粒体数量，改善肥胖患者的心脏收缩力。
-
阻力训练主要保护细胞膜完整性。
-
综合训练能在各种运动类型中普遍提高胰岛素敏感性。
此外，性别差异也存在：在高强度压力下，雌性小鼠表现出更大的代谢灵活性。
总体而言，中高强度的有氧运动对改善心脏代谢最为有效，同时避免了负性重塑。
运动保护线粒体
线粒体是心脏健康的核心，提供能量并调控细胞生存。运动激活了SIRT1/PGC-1α/PI3K/Akt信号通路，增强抗氧化防御、线粒体生成和功能。
此外，运动诱导的线粒体自噬有助于清除受损线粒体，保持健康的线粒体网络，并改善能量生产。
作者指出，HIIT对线粒体结构和功能的改善尤为显著，即使是中等强度的有氧训练，长期也能提升线粒体质量控制。
运动因子：心脏的信使
一个新兴领域是研究运动因子（exerkines）——运动过程中分泌的分子，介导系统性益处。
主要运动因子包括：
-
FGF21：保护线粒体功能，减少心脏重塑，改善心脏结局。
-
Irisin（鸢尾素）：促进线粒体自噬，减少氧化应激，提高心脏耐受性。
-
BAIBA：一种由缬氨酸代谢产生的小分子，减少氧化应激和炎症，改善脂质代谢。
-
CCDC80：抑制促纤维化途径，保护心脏结构。
研究提示，这些分子可能被用于模拟运动益处，尤其适用于无法进行足够运动的心力衰竭患者。
临床意义：运动在心力衰竭治疗中的新角色
本文强调，运动应被视为一种代谢治疗手段，可以恢复衰竭心脏的能量平衡。适度、有针对性的有氧运动可增强线粒体健康，改善底物利用，并防止有害重塑。
不过，作者也强调：“界定运动剂量上限至关重要。”运动量太少，疗效有限；运动过量，则可能增加心脏负担。
最终，运动不仅应作为一种生活方式建议，还应作为一种精准干预手段，用于恢复心肌代谢、延缓心力衰竭进展。
未来的研究应将分子指标（如线粒体功能或运动因子水平）与传统检测方法（如超声心动图）结合，优化运动处方。
结语
Yuanhao Li及其同事的工作揭示了运动在心脏康复中的复杂而充满希望的角色。通过重编程代谢、保护线粒体以及激活系统性信号通路，运动有望彻底改变心力衰竭的管理方式——甚至在疾病发生前就加以预防。
Reference:
Yuanhao Li, Dongli Gao, Peixia Li, Xulei Duan, Youli Liu, Chengyan Wu, Libo Wang, Xuehui Wang
The regulatory role of exercise in heart failure and myocardial energy metabolism: A review.
Biomol Biomed [Internet]. 2025 Feb. 24 [cited 2025 Apr. 28];
Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/12072
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