MyoRep: a novel reporter system to detect early muscle atrophy in vitro and in vivo

Abstract

Muscle atrophy occurs during physiological (i.e., fasting, aging) and pathological (i.e., amyotrophic lateral sclerosis, cancer) conditions and anticipates death. Since not all patients will undergo muscle wasting, it would be highly useful to identify them soon to intervene early. We have studied the promoters/enhancers of a subset of atrophy-related genes or atrogenes upregulated in muscles of rodents during various kinds of atrophy (i.e., disuse, diabetes, cancer, fasting, uremia) for their ability to induce early atrophy. Comparing their upstream non-coding regions, using as backbone MuRF1 promoter (one of the earliest muscle-specific genes induced by wasting), we cloned various promoters upstream of a doubled reporter system (FLuciferase/tdTomato). Through in vitro and in vivo studies in mice subjected to denervation or cancer injection, we selected a sequence (i.e., MyoRep) able to predict atrophy upon cut of the sciatic nerve or cancer. In vivo imaging of MyoRep mice emit a bioluminescent signal earlier than muscle loss. Importantly, MyoRep was unable to sense atrophy during fasting or physiological variations following the circadian rhythms. Since MyoRep can discriminate muscle loss due to pathological conditions from physiological ones anticipating wasting, it represents an unprecedented tool to predict it early in various diseases with local or systemic atrophy.