Inflammation-induced skeletal muscle atrophy in critically ill patients: identification of molecular mechanisms and preventive therapies

Critically ill patients who have to be treated in intensive care units often develop muscular weakness due to neuromuscular organ failure. By investigating the molecular mechanisms of this muscular weakness, the team of Prof. Carmen Birchmeier (MDC), PD Dr. Steffen Weber-Carstens (Charité) and PD Dr. Jens Fielitz (Charité) aims at developing new treatment options in order to shorten the time of intensive care treatment and to improve recovery and physical functioning of patients.

Coordination

Prof. Carmen Birchmeier
Max Delbrück Center for Molecular Medicine

Priv. Doz. Dr. Med. Jens Fielitz
Priv. Doz. Dr. Med. Steffen Weber-Carstens

Charité - Universitätsmedizin Berlin

Three questions for the project team

Carmen Birchmeier
Carmen Birchmeier

What is the central idea of your project?

ICU-acquired weakness is a major sequelae of critical illness. It is the clinical consequence of an acquired neuromuscular organ failure that is characterized by a reduced force capacity per cross sectional muscle area with significant loss of myosin heavy chain (MyHC), and an impaired excitability of nerve and muscle membranes. ICU-acquired weakness aggravates intensive care treatment, delays weaning of mechanical ventilation, prolongs rehabilitation, and results in a sustained limitation of physical independency even years after discharge from intensive care unit. As yet, preventive therapies or uniform therapy programs are not known. Almost all of the papers published on the topic describe phenotypes and mechanisms at the terminal point of the disease. Our previous work indicated that mechanisms resulting in muscle pathology are already activated very early at the onset of a critical illness. We are therefore applying a novel approach in this project. We investigate the early stages of inflammation-induced muscle failure in both an experimental and a clinical setting. In the experimental part of our project, we concentrate on the role of the satellite cells, the stem cells of the muscle, in the development of ICU-acquired weakness. As yet, it is not known whether these cells are activated in inflammation-induced muscle atrophy, and whether satellite cell-mediated mechanisms can ameliorate the outcome of the disease. In an investigator-initiated trial, we will investigate the usefulness, effectiveness and safeness of preventive measures like muscle activation and physiotherapy.

How does your project benefit from BIH?

We examine the medical condition of patients with ICU-acquired muscular organ failure from the various perspectives – at molecular level, in acute critical care, and in chronic/rehabilitation care. For this purpose, we gain muscle biopsy specimens from critically ill patients during defined clinical situation of early critical illness. It is usually difficult to gain muscle biopsy samples in defined clinical situations. Here, we benefit from the opportunity to conduct a clinical study at Charité that is tailored to our specific research objectives. MDC expertise enables us to gain comprehensive insights into molecular disease mechanisms from the valuable muscle biopsy specimens of these patients. In addition, we will be able to evaluate the effect of a preventive therapeutic approach at clinical and molecular level. For ethical and logistical reasons, it is almost impossible to obtain muscle biopsy samples at frequent consecutive intervals from critically ill patients. We will use the expertise of the group in performing proteomic and pathway analyses at the MDC and ECRC to address the molecular pathway at defined stages of inflammatory myopathy in an established mouse model of inflammation-induced muscle failure and in transgenic animals. In addition, we will make use of MDC expertise to assess the role of adult muscle stem cells in inflammatory myopathy. Comparing the data of patients, mice and muscle cells will help to describe the phenotype of inflammatory muscle atrophy in greater detail, uncover pathways involved in the disease process, and open avenues to ameliorate the disease by activating stem cell-mediated repair.

How are your results going to help patients one day?

We still know too little about therapeutic measures that already prevent muscle wasting and weakness in the early stages of critical illnesses. There is some evidence that early physical and occupational therapy improves physical functioning and independence among patients discharged from intensive care. Our translational scientific approach has the potential to improve treatment strategies preventing ICU-acquired muscular organ failure of critically ill patients during acute care and will help to define the optimal care regarding protocol-based physiotherapeutic treatment as well as electrical muscle stimulation early after the onset of critical illness. Our examinations will help to evaluate possible therapies that are based on adult stem cells. All in all, our examinations aim at shortening the time of intensive care treatment and improving long-term recovery and physical functioning of patients after ICU treatment.