Biological sensors and their ability to detect and respond to change in the cellular environment can be modulated by protein scaffolds acting within their interaction network. The skeletal muscle α-actinins have been considered as primarily structural scaffold proteins. However, deficiency of α-actinin-3 due to a common null polymorphism results in predominantly metabolic changes in skeletal muscle function. In this review, we explore the range of phenotypes associated with α-actinin-3 deficiency, and draw supporting evidence from known interaction partners for its role as a scaffold which acts to modulate biological sensors that result in changes in muscle metabolism and structure.