Skeletal muscle regeneration is a complex interplay between various cell types including invading macrophages. Their recruitment to damaged tissues upon acute sterile injuries is necessary for necrotic debris clearance and for coordination of tissue regeneration. This highly dynamic process is characterized by an in situ transition of infiltrating monocytes from an inflammatory (Ly6Chigh) to a repair (Ly6Clow) macrophage phenotype. System-level gene expression analysis revealed that the time course of muscle regeneration, much more than Ly6C status, was correlated with the largest differential gene expression. This indicated that the time course of inflammation was the predominant driving force of macrophage gene expression. These findings validate the dynamic nature of the macrophage response and associate a specific gene signature to predictive specialized functions of macrophages at each step of muscle regeneration. However, the gene regulatory events supporting the sensory and effector functions of macrophages involved in tissue repair are not well understood. Here, we show that the lipid activated transcription factor (TF), PPARg is required for proper skeletal muscle regeneration acting in repair MFs. PPARg controls the expression of the TGFβ family member, GDF3, which in turn regulates the restoration of skeletal muscle integrity by stimulating myoblast cell fusion. In addition, to delineate the order of transcriptional events during monocyte infiltration and in situ macrophage differentiation we generated chromatin accessibility maps using ATAC-seq. We found that a large class of genomic regulatory elements is becoming de novo accessible during monocyte infiltration in the muscle, and motif analysis showed that these sites are highly enriched to the MARE motif, compared to other common macrophage specific motifs. We also identified BACH1, a heme-regulated MARE-binding TF, as a novel regulatory molecule. The contribution of this molecule and downstream targets such as Hmox1, have been evaluated using full body and macrophage-specific knock-outs. Surprisingly, the inactivation of either Bach1 or Hmox1 in macrophages impairs muscle regeneration by altering the dynamics of the macrophage phenotypic transition. In addition, Bach1 deletion leads to transcriptional deregulation of critical inflammatory genes in macrophages upon injury. By using bone marrow-derived macrophages, we found BACH1 to bind extensively to enhancers of these genes, suggesting that fine-tuning of transient inflammatory transcriptional programs in macrophages during tissue injury, largely depend on MARE-binding TFs. Overall, this work establishes PPARg and BACH1 as required environment sensors and transcriptional regulators of muscle infiltrating MFs. Moreover, this work also establishes GDF3 as a secreted extrinsic effector protein acting on myoblasts and serving as a regeneration factor in tissue repair. The importance of the macrophage phenotypic shift and the cell cross-talk of the local muscle tissue with the infiltrating macrophages during tissue regeneration upon injury are also not fully understood and their study lacks adequate methodology. Here, by using an acute sterile skeletal muscle injury model combined with irradiation, bone marrow transplantation and in vivo imaging we show that preserved muscle integrity and cell composition prior to the injury is necessary for repair macrophage phenotypic transition and subsequently for proper and complete tissue regeneration. Importantly, by using a model of in vivo ablation of PAX7 positive cells, we show that this radiosensitive skeletal muscle progenitor pool contributes to macrophage phenotypic transition following acute sterile muscle injury. Taken together, our data suggest the existence of a more extensive and reciprocal cross-talk between muscle tissue compartments, including satellite cells, and infiltrating myeloid cells upon tissue damage. These interactions are shaping the macrophages in-situ phenotypic shift, which is indispensable for normal muscle tissue repair dynamics.