Skeletal muscle wasting after burn is regulated by a decrease in anabolic signaling in the early flow phase.

Following burns a sustained catabolic stress response is activated, resulting in skeletal muscle wasting. A better understanding of the underlying mechanisms of postburn skeletal muscle wasting is essential for the development of preventive and/or therapeutic strategies. Six weeks old female rats underwent a sham, 10% or 40% total body surface area scald burn. Ten days post-injury, severely burned animals gained significantly less weight compared to sham treated and minor burned animals, reflected in a significantly lower ratio of muscle to total body weight for Soleus (SOL) and Extensor Digitorum Longus (EDL) in the severely burned group. Postburn, total fiber number was significantly lower in EDL, while in SOL the amount of type1 fibers significantly increased and type2 fibers significantly decreased. No signs of mitochondrial dysfunction (COX/SDH) or apoptosis (caspase-3) were found. In SOL and EDL, eEF2 and pAKT expression was significantly lower after severe burn. MURF1,2,3 and Atrogin-1 was significantly higher in SOL, whilst in EDL MURF1,2,3 was significantly lower postburn. In both muscles, FOXO3A was significantly lower postburn. This study identified postburn changes in muscle anthropomorphology and proteins involved in pathways regulating protein synthesis and breakdown, with more pronounced catabolic effects in SOL.

Molecular mechanisms of post-burn muscle wasting and the therapeutic potential of physical exercise.

After a severe burn injury, a systemic stress response activates metabolic and inflammatory derangements that, among other, leads to muscle mass loss (muscle wasting). These negative effects on skeletal muscle continue for several months or years and are aggravated by short-term and long-term disuse. The dynamic balance between muscle protein synthesis and muscle protein breakdown (proteolysis) is regulated by complex signalling pathways that leads to an overall negative protein balance in skeletal muscle after a burn injury. Research concerning these molecular mechanisms is still scarce and inconclusive, understanding of which, if any, molecular mechanisms contribute to muscle wasting is of fundamental importance in designing of therapeutic interventions for burn patients as well. This review not only summarizes our present knowledge of the molecular mechanisms that underpin muscle protein balance but also summarizes the effects of exercise on muscle wasting post-burn as promising strategy to counteract the detrimental effects on skeletal muscle. Future research focusing on the pathways causing post-burn muscle wasting and the different effects of exercise on them is needed to confirm this hypothesis and to lay the foundation of therapeutic strategies.

Doxorubicin Impairs Smooth Muscle Cell Contraction: Novel Insights in Vascular Toxicity.

Clinical and animal studies have demonstrated that chemotherapeutic doxorubicin (DOX) increases arterial stiffness, a predictor of cardiovascular risk. Despite consensus about DOX-impaired endothelium-dependent vasodilation as a contributing mechanism, some studies have reported conflicting results on vascular smooth muscle cell (VSMC) function after DOX treatment. The present study aimed to investigate the effects of DOX on VSMC function. To this end, mice received a single injection of 4 mg DOX/kg, or mouse aortic segments were treated ex vivo with 1 µM DOX, followed by vascular reactivity evaluation 16 h later. Phenylephrine (PE)-induced VSMC contraction was decreased after DOX treatment. DOX did not affect the transient PE contraction dependent on Ca2+ release from the sarcoplasmic reticulum (0 mM Ca2+), but it reduced the subsequent tonic phase characterised by Ca2+ influx. These findings were supported by similar angiotensin II and attenuated endothelin-1 contractions. The involvement of voltage-gated Ca2+ channels in DOX-decreased contraction was excluded by using levcromakalim and diltiazem in PE-induced contraction and corroborated by similar K+ and serotonin contractions. Despite the evaluation of multiple blockers of transient receptor potential channels, the exact mechanism for DOX-decreased VSMC contraction remains elusive. Surprisingly, DOX reduced ex vivo but not in vivo arterial stiffness, highlighting the importance of appropriate timing for evaluating arterial stiffness in DOX-treated patients.