Ibuprofen does not impair skeletal muscle regeneration upon cardiotoxin-induced injury.

Muscle regeneration is regulated through interaction between muscle and immune cells. Studies showed that treatment with supra-physiological doses of Non-Steroidal Anti-Inflammatory Drug (NSAID) abolished inflammatory signaling and impaired muscle recovery. The present study examines the effects of pharmacologically-relevant NSAID treatment on muscle regeneration. C57BL/6 mice were injected in the tibialis anterior (TA) with either PBS or cardiotoxin (CTX). CTX-injected mice received ibuprofen (CTX-IBU) or were untreated (CTX-PLAC). After 2 days, Il-1beta and Il-6 expression was upregulated in the TA of CTX-IBU and CTX-PL vs. PBS. However, Cox-2 expression and macrophage infiltration were higher in CTX-PL vs. PBS, but not in CTX-IBU. At the same time, anabolic markers were higher in CTX-IBU vs. PBS, but not in CTX-PL. Nevertheless, ibuprofen did not affect muscle mass or muscle fiber regeneration. In conclusion, mild ibuprofen doses did not worsen muscle regeneration. There were even signs of a transient improvement in anabolic signaling and attenuation of inflammatory signaling.

The muscle contraction mode determines lymphangiogenesis differentially in rat skeletal and cardiac muscles by modifying local lymphatic extracellular matrix microenvironments.

AIM: Lymphatic vessels are of special importance for tissue homeostasis, and increases of their density may foster tissue regeneration. Exercise could be a relevant tool to increase lymphatic vessel density (LVD); however, a significant lack of knowledge remains to understand lymphangiogenesis in skeletal muscles upon training. Interestingly, training-induced lymphangiogenesis has never been studied in the heart. We studied lymphangiogenesis and LVD upon chronic concentric and chronic eccentric muscle contractions in both rat skeletal (Mm. Edl and Sol) and cardiac muscles. METHODS/RESULTS: We found that LVD decreased in both skeletal muscles specifically upon eccentric training, while this contraction increased LVD in cardiac tissue. These observations were supported by opposing local remodelling of lymphatic vessel-specific extracellular matrix components in skeletal and cardiac muscles and protein levels of lymphatic markers (Lyve-1, Pdpn, Vegf-C/D). Confocal microscopy further revealed transformations of lymphatic vessels into vessels expressing both blood (Cav-1) and lymphatic (Vegfr-3) markers upon eccentric training specifically in skeletal muscles. In addition and phenotype supportive, we found increased inflammation (NF-κB/p65, Il-1ß, Ifn-γ, Tnf-α and MPO(+) cells) in eccentrically stressed skeletal, but decreased levels in cardiac muscles. CONCLUSION: Our data provide novel mechanistic insights into lymphangiogenic processes in skeletal and cardiac muscles upon chronic muscle contraction modes and demonstrate that both tissues adapt in opposing manners specifically to eccentric training. These data are highly relevant for clinical applications, because eccentric training serves as a sufficient strategy to increase LVD and to decrease inflammation in cardiac tissue, for example in order to reduce tissue abortion in transplantation settings.

[Molecular mechanisms of exercise-induced cardiovascular adaptations. Influence of epigenetics, mechanotransduction and free radicals]. / Molekulare Mechanismen der Herz- und Gefäßanpassung durch Sport. Einfluss von Epigenetik, Mechanotransduktion und freien Radikalen.

The description of mechanisms underlying exercise-induced heart and vascular bed adaptations reveals and highlights the significance of different mechanical and metabolic stimuli that possibly evoke various short-term and long-term regulations and adaptations of these tissues. In this brief review the molecular mechanisms mediated by free radicals and/or mechanical stimulation and, are therefore involved in the modulation of the extracellular matrix and epigenetics-based regulation of the functional genome will be discussed. In the heart and the vascular bed free radicals play important roles in physiological and pathophysiological processes. Exercise leads on the one hand to increased free radicals but on the other hand improves the antioxidative capacity. This phenomenon shifts the cellular oxidative stress balance and also a variety of signal cascades that mediate physiological and pathophysiological heart and vascular bed adaptations. A similar great significance can be attributed to mechanical stimulation which directly or indirectly influences a variety of signaling cascades. It was demonstrated that exercise alters the molecular composition and architecture of the extracellular matrix which in turn plays an important role in the regulation of different mechanical stimuli-mediating signaling cascades. These alterations in the molecular composition and architecture of the extracellular matrix are of high significance for cellular adaptation processes, possibly also in the sense of epigenetic modulations that are actually only indirectly linked to exercise in cardiovascular tissues. However, there is growing evidence that epigenetic modulations mediated by exercise and physical activity can provoke modifications of the functional genome in heart and vascular beds, comparable to already well-described phenomena, e.g. diet or inflammation.

Regulation of extracellular matrix compounds involved in angiogenic processes in short- and long-track elite runners.

Exercise induces alterations of the extracellular matrix (ECM), e.g. by an increased release of endostatin or by regulation of matrix metalloproteases (MMP)-2/-9, and cathepsin L. To investigate the influence of training status on exercise-induced ECM-processing of angiogenic molecules, alterations of endostatin-, MMP-2, and MMP-9 plasma concentrations during incremental running step tests in male elite short-track (n=6) and male elite long-track runners (n=7) were studied. Three blood samples (pre-exercise, 0, and 1 h post-exercise) were taken from each subject at each running test. In both groups, the basal endostatin plasma concentration was significantly decreased at the second running test, i.e. after the training season. Exercise-related acute alterations of the parameters were also observed only during the second test. In the long-track group, there was a significant increase in endostatin at 0 h and of MMP-2 at 1 h post-exercise. In the short-track group, only MMP-9 was significantly increased at 0 h post-exercise. Cathepsin L was increased at 0 h post-exercise. In conclusion, regular exercise performance decreases the basal endostatin plasma concentration, facilitates ECM-processing of angiogenic molecules by regular performance, and seems to be dependent on the kind of training.