Adult skeletal muscle is a highly plastic tissue that adapts its size to environmental cues and functional demand depending on such as external loads, neural activity, hormones and substrate supply. Understanding the molecular pathways that regulate gain and loss of muscle mass is crucial for treating muscle wasting associated to conditions such as cancer and other chronic diseases (cachexia) and aging (sarcopenia). The need to handle mechanical signals is particularly obvious in muscle cells which are constantly exposed to external forces and generate forces themselves. Muscle tissue depends on mechanical stimulation for its homeostasis: chronically decreased mechanical loads (immobilization, denervation) lead to muscle atrophy and increased loads to muscle hypertrophy (compensatory hypertrophy). From a clinical point of view, several chronic diseases are characterized by muscle wasting as well as reduced fatigue resistance which consequently results into decreased muscular activity (i.e. decreased mechanical stimulation), leading to a vicious circle further worsening muscle performance and patients' quality of life. For instance, it has been reported that physical activity spontaneously declines in cancer patients affected by cachexia, while it has been shown that increasing physical activity, even post-diagnosis, improves prognosis in these patients. While significant progress has been made in understanding the signaling pathways that control muscle mass, the molecules that translate muscle load into signals that support hypertrophy/atrophy are unclear. In a search for novel factors involved in controlling muscle mass in response to workload, our recent findings identified the transcription factor Srf (Serum Response Factor). Using a mouse model of conditional and inducible deletion of Srf within adult myofibers, we have shown that Srf loss leads to blunted overload-induced muscle hypertrophy and to increased denervation-induced atrophy, a situation of “mechanical silencing” of the muscle. Importantly, Srf is required for muscle hypertrophy in response to increased loading but is dispensable for myrAkt induced hypertrophy, which occurs in the absence of increased mechanical signals. In addition upon denervation-induced atrophy, we showed that Srf activity decreases while it did not vary in muscle atrophic situations which do not rely on loss of activity (such as caloric restriction), thus demonstrating a specific contribution of Srf in lack of activity-induced atrophy. In a pathological context, we demonstrated that exercise fully rescues cachexia. Based on our observation that Srf target genes are downregulated in cachexia, we hypothesize that Srf could contribute to the rescue of cachexia by exercise. Taken together, these data point towards Srf as a good candidate transcription factor translating mechanical signals into a transcriptional program which regulates muscle mass in both physiological and pathological conditions. Our objective is to study the inter-relations between Srf and mechanotransduction in the context of skeletal muscle tissue using original in vivo models relevant in muscle physiology and pathophysiology and in vitro cellular models allowing biophysical and molecular studies. We aim at: - Defining the mechanical signals that can be interpreted by Srf - Identifying pathways/molecules upstream and downstream of Srf in the mediation of mechanical cues - Determining the role of Srf in the amelioration of cachexia by exercise. The present proposal relies on the association of three teams with complementary expertise: transcriptional regulation (Team #1), muscle physiology and physiopathology (Team #1 and #3), biophysics and cellular biomechanics (Team #2).