Skeletal muscle dysfunctions in pulmonary arterial hypertension: Effects of aerobic exercise training

Drummond FR, Leite LB, De Miranda DC, et al. Skeletal muscle dysfunctions in pulmonary arterial hypertension: Effects of aerobic exercise training. Frontiers in Physiology. 2023;14. doi:10.3389/fphys.2023.1148146

Link to Original Article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10076612/

Key Points

1. Pulmonary arterial hypertension (PAH) is associated with skeletal muscle myopathy, atrophy, and impaired exercise tolerance. Aerobic exercise training (AET) has been recommended as a non-pharmacological therapy for PAH to induce skeletal muscle adaptations, leading to improved physical exertion tolerance and quality of life in patients with PAH.

2. Studies have shown that moderate-to-high intensity AET causes beneficial adaptations to the cardiovascular system in individuals affected by PAH, maintaining right ventricular function, stroke volume, and cardiac output.

3. Skeletal muscle impairments contribute to limiting exercise capacity, increasing sedentary behavior, and reducing activities of daily living in patients with PAH. Muscle atrophy is attributed to elevated inflammatory response, inhibition of anabolic pathways, hypoxemia, abnormalities in mitochondrial function, and imbalance in protein synthesis and degradation.

4. PAH causes an imbalance between synthesis and degradation of structural and contractile proteins in the myofibrils, with elevated levels of atrogin-1 and muscle RING-finger protein-1 observed in the quadriceps of patients with PAH, suggesting the contribution of UPS-mediated proteolysis to skeletal muscle atrophy in these patients.

5. Mechanisms underlying the effects of AET on skeletal muscle adaptations in PAH include the induction of myokines, prevention or attenuation of inhibition of anabolic hormone pathways, mitigation of muscle hypoxemia, and enhancement of mitochondrial function and structure.

6. Current pharmacological therapies for PAH have positive effects, but AET has been shown to trigger positive adaptations in individuals with PAH, leading to enhanced functional and exercise capacity, ventilatory efficiency, global cardiac function, arterial and myocardial elasticity, antioxidative and anti-inflammatory defense, and cardiopulmonary remodeling.

Introduction

The introduction of the mini-review discusses the benefits of aerobic exercise training (AET) for individuals, including those with cardiovascular diseases such as pulmonary arterial hypertension (PAH). It highlights that moderate to high-intensity AET can lead to positive adaptations in the cardiovascular system, particularly in maintaining right ventricular function (RV) and preserving stroke volume and cardiac output in individuals with PAH. The circumstances imposed by PAH can impair quality of life and lead to intolerance to physical effort, with complex underlying mechanisms involving central (stroke volume and cardiac output) and peripheral (blood flow, endothelial and skeletal muscle functions) adverse adaptations. While studies have shown the benefits of AET in improving physical effort tolerance in individuals with PAH, there is a lack of research addressing the underlying mechanisms involved in skeletal muscle adaptation. Therefore, the mini-review aims to highlight the cellular and molecular pathways involved in the skeletal muscle adaptations to AET in patients with PAH.

Pulmonary arterial hypertension

The article discusses the impact of pulmonary arterial hypertension (PAH), the most common subtype of pulmonary hypertension, on cardiovascular and respiratory function. The incidence of PAH affects 1.1 to 17.6 million adults per year and prevalence of PAH is 6.6 to 26.0 million adults. PAH has a poor prognosis and the pathophysiology involves restricted blood flow, endothelial dysfunction, and increased contractility of small pulmonary arteries. PAH is typically diagnosed in the third or fourth decade of life, but children can also be diagnosed with more severe prognosis. The diagnosis of PAH is clinically defined as pulmonary arterial pressure >20 mmHg at rest with normal left atrial pressure and pulmonary vascular resistance of ≥3 Wood units. The etiology of PAH is caused by restricted blood flow in the pulmonary arterial circulation. The chronic increase in pulmonary vascular resistance leads to right ventricular afterload and hypertrophy, resulting in adverse remodeling and right ventricular failure, a major cause of death in PAH patients. The symptoms typically include dyspnea, fatigue, and exercise intolerance, which has been attributed to low cardiac output and respiratory dysfunction, but also involves abnormalities in skeletal and respiratory muscles. Despite this, aerobic exercise training has been found to increase oxygen consumption, improve skeletal muscle cross-sectional area, and enhance exercise tolerance in PAH patients. The potential benefits of aerobic exercise training on maintaining right ventricular function, increasing stroke volume, and cardiac output in individuals affected by PAH are emphasized.

Pulmonary arterial hypertension and skeletal muscle

The skeletal muscle adaptations to aerobic exercise training in patients with pulmonary arterial hypertension (PAH) involve several cellular and molecular pathways. Traditionally, decreased muscle mass in PAH patients leads to physical effort intolerance due to low cardiac output and reduced oxygen and nutrient supply to peripheral systems. Skeletal muscle impairments contribute to exercise capacity limitations and reduced daily activities. Imbalances in the synthesis and degradation of structural and contractile proteins in the myofibrils, particularly through the ubiquitin-proteasome system, contribute to skeletal muscle atrophy in PAH. Elevated levels of proinflammatory cytokines and systemic inflammation can damage muscle contractile proteins, induce proteolysis, and lead to muscle atrophy and decreased physical performance. Additionally, hypoxemia, abnormalities in mitochondrial function, and inhibition of anabolic pathways through insulin signaling and testosterone reduction contribute to PAH-related myopathy. Studies have shown reduced expression of PGC1α and mitochondrial DNA, as well as negative changes in electron transport chain supercomplexes in skeletal muscles of PAH animal models. Although the underlying mechanisms of skeletal muscle dysfunction in PAH are not fully understood, it is clear that PAH has a significant impact on skeletal muscle and the quality of life of patients. Therefore, further research to understand these mechanisms and develop therapies to mitigate muscular damage in PAH patients is warranted.

Pulmonary arterial hypertension and physical exercise

The research paper discusses the potential benefits of aerobic exercise training (AET) in patients with pulmonary arterial hypertension (PAH) and its impact on skeletal muscle adaptations, right ventricular function, and overall cardiac output. It highlights the limitations of current pharmacological therapies for PAH due to lack of availability and non-responders to medication, emphasizing the need for alternative treatments to enhance patients' quality of life. AET has been recommended as the best non-pharmacological therapeutic tool, triggering positive adaptations in PAH individuals, including improved exercise capacity, cardiac function, and cardiopulmonary remodeling. However, there is limited understanding of the underlying cellular and molecular mechanisms of AET on skeletal muscles in PAH. Some evidence suggests that AET can influence myokine secretion, induce anti-inflammatory responses, prevent muscle atrophy, and enhance muscle hypertrophy. Moreover, AET may attenuate muscle hypoxemia, improve muscle oxygenation, and enhance mitochondrial function in PAH patients. The paper also highlights the similarities in skeletal muscle impairments between PAH, chronic obstructive pulmonary disease, and heart failure, and how physical exercise can mitigate these effects. A previous clinical study on patients with idiopathic PAH who received 12 weeks of exercise training showed increased muscular resistance, as evident by the 30% increase in the number of blood capillaries and the 39% augment in the absorbance of the oxidative enzyme succinate dehydrogenase in the quadriceps. Based on the study, it is suggested that AET improves both function and structure of mitochondria. Overall, the literature proposes several mechanisms contributing to the structural and functional changes in skeletal muscle in PAH patients undergoing AET, presenting a promising non-pharmacological approach for improving the health of individuals with PAH.

Perspectives

Figure 1.

Potential mechanisms underlying the effects of aerobic exercise training on skeletal muscle atrophy and weakness in PAH

The mini-review discusses the cellular and molecular pathways involved in skeletal muscle adaptations to aerobic exercise training (AET) in patients with pulmonary arterial hypertension (PAH). Despite the lack of comprehensive studies on skeletal muscle adaptations to AET in PAH patients, it is observed that AET can potentially protect against muscle atrophy, increase muscle capillarization, and improve mitochondrial function. The review emphasizes the need for studies focusing on the effects of physical exercise on skeletal muscle structural, cellular, and molecular adaptations in PAH patients. These include morphological changes, alterations in muscle fiber type and connective tissue, as well as molecular changes such as alterations in contractile units, muscle inflammatory state, oxidative stress, signaling pathways for cell survival and death, mitochondrial biogenesis and metabolism, and epigenetic analyses, particularly related to miRNAs associated with contractile mechanics. Understanding these mechanisms is important to develop strategies to mitigate the damage caused by PAH. Additionally, the review points out the potential benefits of AET in maintaining right ventricular function and its impact on stroke volume and cardiac output in individuals affected by PAH. While more comprehensive studies are needed, the review suggests that AET has the potential to positively influence skeletal muscle adaptations and right ventricular function in PAH patients.