Extramyocellular interleukin-6 influences skeletal muscle mitochondrial physiology through canonical JAK/STAT signaling pathways.

Interleukin-6 (IL-6) is a pleiotropic cytokine that has been shown to be produced acutely by skeletal muscle in response to exercise, yet chronically elevated with obesity and aging. The mechanisms by which IL-6 influences skeletal muscle mitochondria acutely and chronically are unclear. To better understand the influence of extramyocellular IL-6 on skeletal muscle mitochondrial physiology, we treated differentiated myotubes with exogenous IL-6 to evaluate the dose- and duration-dependent effects of IL-6 on salient aspects of mitochondrial biology and the role of canonical IL-6 signaling in muscle cells. Acute exposure of myotubes to IL-6 increased the mitochondrial reactive oxygen species (mtROS) production and oxygen consumption rates (JO2 ) in a manner that was dependent on activation of the JAK/STAT pathway. Furthermore, STAT3 activation by IL-6 was partly attenuated by MitoQ, a mitochondrial-targeted antioxidant, suggesting that mtROS potentiates STAT3 signaling in skeletal muscle in response to IL-6 exposure. In concert with effects on mitochondrial physiology, acute IL-6 exposure induced several mitochondrial adaptations, consistent with the stress-induced mitochondrial hyperfusion. Exposure of myotubes to chronically elevated IL-6 further increased mtROS with eventual loss of respiratory capacity. These data provide new evidence supporting the interplay between cytokine signaling and mitochondrial physiology in skeletal muscle.

Influence of omega-3 fatty acids on skeletal muscle protein metabolism and mitochondrial bioenergetics in older adults.

Omega-3 polyunsaturated fatty acids (n3-PUFA) are recognized for their anti-inflammatory effects and may be beneficial in the context of sarcopenia. We determined the influence of n3-PUFA on muscle mitochondrial physiology and protein metabolism in older adults. Twelve young (18-35 years) and older (65-85 years) men and women were studied at baseline. Older adults were studied again following n3-PUFA supplementation (3.9g/day, 16 weeks). Muscle biopsies were used to evaluate respiratory capacity (high resolution respirometry) and oxidant emissions (spectrofluorometry) in isolated mitochondria. Maximal respiration was significantly lower in older compared to young. n3-PUFA did not change respiration, but significantly reduced oxidant emissions. Participants performed a single bout of resistance exercise, followed by biopsies at 15 and 18 hours post exercise. Several genes involved in muscle protein turnover were significantly altered in older adults at baseline and following exercise, yet muscle protein synthesis was similar between age groups under both conditions. Following n3-PUFA supplementation, mixed muscle, mitochondrial, and sarcoplasmic protein synthesis rates were increased in older adults before exercise. n3-PUFA increased post-exercise mitochondrial and myofibrillar protein synthesis in older adults. These results demonstrate that n3-PUFA reduce mitochondrial oxidant emissions, increase postabsorptive muscle protein synthesis, and enhance anabolic responses to exercise in older adults.

Pulmonary vascular collagen content, not cross-linking, contributes to right ventricular pulsatile afterload and overload in early pulmonary hypertension.

Hypoxic pulmonary hypertension (HPH) is associated with pulmonary artery (PA) remodeling and right ventricular (RV) overload. We have previously uncovered collagen-mediated mechanisms of proximal PA stiffening in early HPH by manipulating collagen degradation and cross-linking using a transgenic mouse strain and a potent collagen cross-link inhibitor, ß-aminopropionitrile (BAPN). However, the roles of collagen in distal PA remodeling, overall RV afterload, and RV hypertrophy in HPH remain unknown. Here, we used the same experimental strategy to investigate the effect of pulmonary vascular collagen content and cross-linking on steady and pulsatile RV afterload and on RV hypertrophy in early HPH. Collagenase-resistant mice (Col1a1R/R) and their littermate controls (Col1a1+/+) were exposed to normobaric hypoxia for 10 days with or without BAPN treatment. In vivo pulmonary vascular impedance, a comprehensive measure of RV afterload, was measured via simultaneous RV catheterization and echocardiography. Morphology and collagen accumulation were examined using histological techniques and ELISA in lungs and RVs. In both mouse strains, BAPN did not limit increases in pulmonary arterial pressure or pulmonary vascular resistance, indicating a negligible effect of either collagen content or cross-linking on steady RV afterload. However, BAPN prevented the increase in pulse pressure and RV hypertrophy in Col1a1+/+ mice and these effects were absent in Col1a1R/R mice, suggesting a role for PA collagen content, not cross-linking, in the pulsatile RV afterload. Moreover, we found a significant correlation between pulse pressure and RV hypertrophy, indicating an important role for pulsatile RV afterload in RV overload in early HPH. NEW & NOTEWORTHY: The present study found an important role for collagen content, but not collagen cross-linking, in the pulsatile right ventricular (RV) afterload, which is correlated with RV hypertrophy. These results uncover a new collagen-mediated mechanical mechanism of RV dysfunction in early pulmonary hypertension progression. Furthermore, our results suggest that measures and metrics of pulsatile hemodynamics such as pulse pressure and pulse wave velocity are potentially important to cardiovascular mortality in patients with pulmonary hypertension.