Pulmonary arterial hypertension (PAH) is a rare and progressive disease characterized by pathological remodeling of the pulmonary arteries, resulting in increased pulmonary vascular resistance and right ventricular overload. This condition triggers common symptoms such as dyspnea and exercise intolerance, compromising thus the quality of life of individuals affected by this pathology. Skeletal muscle atrophy is one of the main determinants of these symptoms, which is mediated by an imbalance between protein synthesis and degradation, triggered by adverse systemic adaptations promoted by PAH, such as decreased blood perfusion and increased inflammation. This review addresses the main cellular and molecular mechanisms that potentially trigger or inhibit protein degradation pathways, and how they interact in the context of PAH. Furthermore, we focus on physical exercise as a non-pharmacological approach capable of modulating muscle atrophy induced by PAH.