Early neonatal nutrition affects the rate and extent of muscle growth and fiber hypertrophy in calves. The objective of the experiment was to examine the effect of caloric intake on LM, infraspinatus (INF) and semitendinosus (ST) fiber cross-sectional area (CSA), fiber type and muscle gene expression in neonatal heifers. Newborn Holstein heifers were assigned to a high nutritional plane (HNP; 28% CP, 25% fat, n = 5) or low nutritional plane (LNP; 20% CP, 20% fat, n = 5) milk replacer diet for 8 wks. Calves were pair-fed equivalent amounts of grain (25% CP, 4% fat) beginning at wk 5. Caloric intake supported ADG of 220 g/d and 771 g/d for the LNP and HNP heifers, respectively. Heifers were euthanized at 8 wks of age and samples of LM, INF and ST were collected. Gene expression was measured by RT-qPCR. Data were analyzed by ANOVA for the main effect of diet, muscle and their interaction with post-hoc Tukey separation of means. Plane of nutrition differentially affected muscle fiber hypertrophy with HNP LM and ST fiber cross-sectional area (CSA) larger (P < 0.05) than LNP. No differences in CSA were noted between HNP and LNP INF. The smaller LNP LM and LNP ST sizes were reflected by greater (P < 0.05) numbers of fibers/mm². Pax7 expression is 38% greater (P < 0.05) in HNP LM than LNP LM and BTG2, E2F6 and myogenin mRNA amounts are 60% greater (P < 0.05) suggesting that muscle stem and progenitor cells are active and supplying the growing fiber with myonuclei. Messager levels of IGF-I are greater (P < 0.05) in HNP LM than LNP LM further supporting increased fiber hypertrophy. No differences (P > 0.05) were observed in the protein degradation enzyme genes, FOX03, atrogin or MuRF, indicating that protein accretion is due to elevated protein synthesis. Diet can serve as an epigenetic modifier of phenotype. Calves maintained on the LNP diet expressed lower (P < 0.05) amounts of the histone deacetylase genes, HDAC1 and HDAC3, and the lysine-specific demethylase, KDM2A, in the LM than their HNP counterparts. Altered expression of epigenome modifiers provides evidence for diet-induced changes in the muscle fiber chromatin architecture that may contribute to long-term metabolic responses.