Abstract
Myofiber atrophy occurs with aging and in many diseases but the underlying mechanisms are incompletely understood. Here, we have used >1,100 muscle-targeted RNAi interventions to comprehensively assess the function of 447 transcription factors in the developmental growth of body wall skeletal muscles in Drosophila. This screen identifies new regulators of myofiber atrophy and hypertrophy, including the transcription factor Deaf1. Deaf1 RNAi increases myofiber size whereas Deaf1 overexpression induces atrophy. Consistent with its annotation as a Gsk3 phosphorylation substrate, Deaf1 and Gsk3 induce largely overlapping transcriptional changes that are opposed by Deaf1 RNAi. The top category of Deaf1-regulated genes consists of glycolytic enzymes, which are suppressed by Deaf1 and Gsk3 but are upregulated by Deaf1 RNAi. Similar to Deaf1 and Gsk3 overexpression, RNAi for glycolytic enzymes reduces myofiber growth. Altogether, this study defines the repertoire of transcription factors that regulate developmental myofiber growth and the role of Gsk3/Deaf1/glycolysis in this process.
Highlights
Skeletal muscle is a key tissue of the human body accounting for approximately 40–50% of the total body mass
Only few of the ~1,400 human transcription factors have been studied for their capacity to modulate skeletal muscle mass
Because of the reduced genetic redundancy and the 40-fold increase in muscle mass that occurs in development, larval body wall skeletal muscles provide an ideal setting for identifying interventions that induce myofiber atrophy and hypertrophy
Summary
Skeletal muscle is a key tissue of the human body accounting for approximately 40–50% of the total body mass. When muscle protein synthesis exceeds protein degradation, this leads to skeletal muscle hypertrophy, which typically results from an increase in myofiber size. Myofiber atrophy occurs when protein breakdown is excessive or protein synthesis is insufficient [1,2]. This occurs following inactivity, fasting, as a side effect of many pharmacological treatments, and in the course of many degenerative diseases such as cancer cachexia, chronic heart disease, diabetes, sepsis, infections, chronic obstructive pulmonary disease, and renal failure [3]. Prevention of skeletal muscle mass loss in tumor-bearing mice results in increased survival even if cancer progression is not halted [4,5,6]. Despite great strides towards understanding the mechanisms responsible for muscle wasting, incomplete knowledge in this area has hampered the development of suitable therapies
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