Background Critical illness myopathy (CIM) and polyneuropathy (CIP) are a common complication of critical illness. Both cause intensive-care-unit-acquired (ICU-acquired) muscle weakness (ICUAW) which increases morbidity and delays rehabilitation and recovery of activities of daily living such as walking ability. Focused physical rehabilitation of people with ICUAW is, therefore, of great importance at both an individual and a societal level. A recent systematic Cochrane review found no randomised controlled trials (RCT), and thus no supporting evidence, for physical rehabilitation interventions for people with defined CIP and CIM to improve activities of daily living. Therefore, the aim of our study is to compare the effects of an additional physiotherapy programme with systematically augmented levels of mobilisation with additional in-bed cycling (as the parallel group) on walking and other activities of daily living.

Background Critical illness myopathy (CIM) and polyneuropathy (CIP) are a common complication of critical illness. Both cause intensive-care-unit-acquired (ICU-acquired) muscle weakness (ICUAW) which increases morbidity and delays rehabilitation and recovery of activities of daily living such as walking ability. Focused physical rehabilitation of people with ICUAW is, therefore, of great importance at both an individual and a societal level. A recent systematic Cochrane review found no randomised controlled trials (RCT), and thus no supporting evidence, for physical rehabilitation interventions for people with defined CIP and CIM to improve activities of daily living. Therefore, the aim of our study is to compare the effects of an additional physiotherapy programme with systematically augmented levels of mobilisation with additional in-bed cycling (as the parallel group) on walking and other activities of daily living.

Transforming growth factor beta 1 (TGF-beta1) ist ein multifunktionales Zytokin, welches eine Rolle in der Sepsis und in der Sepsis-induzierten Myopathie spielen könnte. Weiterhin könnten erhöhte TGF-beta1-Level zur Muskelschwäche, die mit der Intensivpflege assoziiert ist (engl. intensiv care unit-acquired weakness, ICUAW), beitragen. Der TGF-beta1- Signalweg wurde in Skelettmuskelbiopsien von ICUAW-Patienten heraufreguliert. Secreted frizzled related protein 2 (SFRP2) wurde in einer Gen-Set-Anreicherungsanalyse als das am höchsten regulierte Gen identifiziert. Im Mausmodell führten Sepsis und Hunger zu einer verringerten Sfrp2-Expression, während dies in der Denervation-induzierten Skelettmuskelatrophie nicht festzustellen war. In differenzierten C2C12-Myotuben führte TGF-beta1 zu einer verringerten Sfrp2-mRNA- und Proteinexpression. Luciferase-Assays deuteten auf eine TGF-beta1-abhängige Herunterregulation von Sfrp2 hin, welche auf Promoterebene durch mögliche negative regulatorische Elemente im Sfrp2-Promoter vermittelt wurde. Weiterhin wurde eine TGF-beta1 induzierte Muskelatrophie durch transkriptionelle Repression der myosin heavy chain Gene beobachtet. Im Gegensatz dazu veränderte TGF-beta1 nicht den proteasomalen Abbau muskulärer Proteine. Die Genexpression von Tripartite motif containing 63 und F-box only protein 32 war hingegen leicht herunterreguliert. TGF-beta1-induzierte Atrophie in differenzierten C2C12-Myotuben wurde teilweise durch rekombinantes Sfrp2 aufgehoben. Weiterhin wurde eine direkte physikalische Interaktion zwischen Sfrp2 und TGF-beta1 gefunden, welche diesen Effekt verursacht haben könnte. Zusammengefasst lässt sich feststellen, dass der TGF-beta1- Signalweg eine wichtige Rolle in der ICUAW durch Inhibition der myosin heavy chain Expression spielt. TGF-beta1-abhängige Herunterregulation von Sfrp2 könnte zu einer Feedback-Antwort, die das Ausmaß der Atrophie durch TGF-beta1 verstärkt, führen. / Transforming growth factor beta 1 (TGF-beta1) is a multifunctional cytokine that may play a role in sepsis and in sepsis-induced myopathy. Our group speculated that increased TGF-beta1 could contribute to intensive care (ICU)-acquired weakness (ICUAW), a catastrophic muscle disease in critically ill patients. We found that TGF-beta1 signaling in skeletal muscle biopsies of ICUAW patients was upregulated. Secreted frizzled related protein 2 (SFRP2) was the most regulated gene identified by gene set enrichment analysis (GSEA). I then studied the regulation and function of SFRP2 in different skeletal muscle atrophy models. In three mouse models, downregulated Sfrp2 expression was observed in sepsis and starvation, but not in denervation-induced skeletal muscle atrophy. In differentiated C2C12 myotubes, TGF-beta1 downregulated Sfrp2 expression on both mRNA and protein levels. Luciferase assays suggested that TGF-beta1-dependent downregulation of Sfrp2 was mediated at the promoter level through possible negative regulatory elements in the Sfrp2 promoter. I also observed that TGF-beta1-induced muscle atrophy was accompanied by transcriptional repression of myosin heavy chain genes. In contrast, TGF-beta1 did not increase proteasomal degradation of muscular proteins since gene expression of Tripartite motif containing 63 (Trim63) and F-box only protein (Fbxo32) was not upregulated; instead, they were slightly downregulated. TGF- beta1-induced differentiated C2C12 myotube atrophy was partially reversed by recombinant Sfrp2. This inhibitory effect could have resulted from direct interaction between Sfrp2 and TGF-beta1, since I found a physical interaction between these two proteins. Taken together, TGF-beta1 signaling pathway could play an important role in ICUAW via inhibition of myosin heavy chain expression. TGF-beta1-dependent downregulation of Sfrp2 may establish a feedback loop augmenting the atrophic effect of TGF-beta1.