Science · 2001 · 3.5K citations · 13 references
Life SciencesBiochemistryMolecular BiologyBiochemical GeneticsGene ExpressionSignal TransductionMuscle PathologyMuscle PhysiologyE3 Ubiquitin Ligase Substrate RecognitionMuscle AtrophyMuscle Atrophy MechanismsRegulation By E3 Ubiquitin LigasesScf Ubiquitin Ligase ComplexSkeletal Muscle AtrophyUbiquitin BindingUbiquitin System
Skeletal muscle undergoes atrophy in response to reduced activity and load. The study aimed to identify candidate molecular mediators of muscle atrophy through transcript profiling. Transcript profiling revealed two ubiquitin ligases—MuRF1 and MAFbx, an SCF family member—as key mediators. Only a small subset of up‑regulated genes was common across all atrophy models, and overexpression of MAFbx induced atrophy while knockout of MAFbx or MuRF1 conferred resistance, indicating these proteins as potential drug targets.
Skeletal muscle adapts to decreases in activity and load by undergoing atrophy. To identify candidate molecular mediators of muscle atrophy, we performed transcript profiling. Although many genes were up-regulated in a single rat model of atrophy, only a small subset was universal in all atrophy models. Two of these genes encode ubiquitin ligases: Muscle RING Finger 1 ( MuRF1 ), and a gene we designate Muscle Atrophy F-box ( MAFbx ), the latter being a member of the SCF family of E3 ubiquitin ligases. Overexpression of MAFbx in myotubes produced atrophy, whereas mice deficient in either MAFbx or MuRF1 were found to be resistant to atrophy. These proteins are potential drug targets for the treatment of muscle atrophy.
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