Skeletal Muscle Dysfunction in Experimental Pulmonary Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a serious, progressive, and often fatal disease that is in urgent need of improved therapies that treat it. One of the remaining therapeutic challenges is the increasingly recognized skeletal muscle dysfunction that interferes with exercise tolerance. Here we report that in the adult rat Sugen/hypoxia (SU/Hx) model of severe pulmonary hypertension (PH), there is highly significant, almost 50%, decrease in exercise endurance, and this is associated with a 25% increase in the abundance of type II muscle fiber markers, thick sarcomeric aggregates and an increase in the levels of FoxO1 in the soleus (a predominantly type I fiber muscle), with additional alterations in the transcriptomic profiles of the diaphragm (a mixed fiber muscle) and the extensor digitorum longus (a predominantly Type II fiber muscle). In addition, soleus atrophy may contribute to impaired exercise endurance. Studies in L6 rat myoblasts have showed that myotube differentiation is associated with increased FoxO1 levels and type II fiber markers, while the inhibition of FoxO1 leads to increased type I fiber markers. We conclude that the formation of aggregates and a FoxO1-mediated shift in the skeletal muscle fiber-type specification may underlie skeletal muscle dysfunction in an experimental study of PH.

Oxidative Stress and FOXO-1 Relationship in Stage III Periodontitis

“…As a result of studies examining the role of FOXO1 in antioxidant defense, it has been revealed that it is associated with some systemic inflammatory diseases such as cardiovascular diseases [ 16 ], brain diseases [ 17 ], and skeletal muscle diseases [ 18 ], but there is not enough data on its relationship with periodontitis. In this study, we tested the hypothesis that the FOXO1 may regulate antioxidant mechanisms in periodontal inflammation and aimed to evaluate the salivary and serum FOXO1 and 8-OHdG levels in advanced periodontitis patients.…”

Pulmonary hypertension alters blood flow distribution and impairs the hyperemic response in the rat diaphragm

“…Impaired strength, oxygenation, and mitochondrial function in peripheral skeletal muscle (Bauer et al, 2007;Mainguy et al, 2010;Schulze et al, 2021;Schulze et al, 2022;Malenfant et al, 2015a;Malenfant et al, 2015b;Dimopoulos et al, 2013) independent of reduced cardiac output support the notion of vascular dysfunction beyond the pulmonary circulation. It has been suggested that diaphragm contractile dysfunction precedes central hemodynamic compromise (Kosmas et al, 2022), however, the effects of PH on bulk and regional diaphragm perfusion have not been investigated directly. In order to sustain diaphragmatic contractile function, there must be a tight coupling of O 2 delivery ( _ QO 2 )-to-O 2 demand ( _ VO 2 ).…”