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We investigated the shuttling of Homer protein isoforms identified in soluble (cytosolic) vs. insoluble (membrane–cytoskeletal) fraction and Homer protein–protein interaction/activation in the deep postural calf <i>soleus</i> (<i>SOL)</i> and non-postural <i>gastrocnemius</i> (<i>GAS</i>) muscles of <i>het^−/−</i> mice, i.e., mice with an autosomal recessive variant responsible for a vestibular disorder, in order to further elucidate a) the underlying mechanisms of disrupted vestibular system-derived modulation on skeletal muscle, and b) molecular signaling at respective neuromuscular synapses. Heterozygote mice muscles served as the control (CTR). An increase in Homer cross-linking capacity was present in the <i>SOL</i> muscle of <i>het^−/−</i> mice as a compensatory mechanism for the altered vestibule system function. Indeed, in both fractions, different Homer immunoreactive bands were detectable, as were Homer monomers (~43–48 kDa), Homer dimers (~100 kDa), and several other Homer multimer bands (>150 kDA). The <i>het^−/− GAS</i> particulate fraction showed no Homer dimers vs. <i>SOL</i>. The <i>het^−/− SOL</i> soluble fraction showed a twofold increase (+117%, <i>p</i> ≤ 0.0004) in Homer dimers and multimers. Homer monomers were completely absent from the <i>SOL</i> independent of the animals studied, suggesting muscle-specific changes in Homer monomer vs. dimer expression in the postural <i>SOL</i> vs. the non-postural <i>GAS</i> muscles. A morphological assessment showed an increase (+14%, <i>p</i> ≤ 0.0001) in slow/type-I myofiber cross-sectional area in the <i>SOL</i> of <i>het^−/−</i> vs. CTR mice. Homer subcellular immuno-localization at the neuromuscular junction (NMJ) showed an altered expression in the <i>SOL</i> of <i>het^−/−</i>mice, whereas only not-significant changes were found for all Homer isoforms, as judged by RT-qPCR analysis. Thus, muscle-specific changes, myofiber properties, and neuromuscular signaling mechanisms share causal relationships, as highlighted by the variable subcellular Homer isoform expression at the instable NMJs of vestibular lesioned <i>het^−/−</i> mice.