Beta 2 spectrin (B2S) and ankyrin B (AnkB) are cytoskeletal scaffolding proteins, which separately or as a complex stabilize membrane proteins. The B2S-AnkB complex was proposed to regulate skeletal muscle (SKM) integrity by maintaining the membrane localization of dystrophin, which deficits lead to X-linked Becker and Duchenne muscular dystrophies. However, mice lacking AnkB or B2S in SKM exhibit endurance exercise deficits without overt loss of membrane dystrophin. Notably, we uncovered that AnkB promotes mitochondrial dynamics and fatty acid oxidation to support energetic demands during exercise. Based on the phenotypic similarities between SKM-specific B2S knockout (KO) and AnkB KO mice, we postulated that B2S modulates SKM energetics via a similar mechanism that depends on its binding to AnkB. Here, we used unbiased and targeted approaches to define the roles of B2S in SKM energetics. I profiled gene expression in gastrocnemius (GC) muscle of WT, B2S-KO mice, and of knock-in mice expressing the Y1874A (YA) B2S mutation, which disrupts AnkB binding. RNA-seq analysis revealed changes in transcriptional levels of genes and pathways related to oxidative phosphorylation and ATP production in B2S-KO SKM. In contrast, YA SKM showed altered expression of genes encoding structural proteins. These findings and my data that B2S-KO SKM fibers with normal mitochondria content have a hyperpolarized mitochondria network, the opposite of AnkB-KO fibers, indicate that AnkB and B2S support SKM bioenergetics via parallel, independent pathways.