The characterization of fibro/adipogenic progenitor cells (FAPs) in the skeletal muscle has contributed to modify the monocentric view of muscle regeneration beyond muscle satellite cells (MuSCs). Now, we are aware that each population of the muscle niche plays a critical role in modulating homeostasis and regeneration. In the healthy muscle, FAPs contribute to maintain tissue homeostasis and assist MuSCs to cope with limited insults. Here, FAPs sense and integrate niche signals that keep in check their differentiation potential. The disruption of these niche cues leads to FAP differentiation into adipocytes and fibroblasts, both detrimental hallmarks of a large variety of muscle wasting diseases. FAP biology is still in its infancy, and current efforts are focused on the understanding of the molecular circuits governing their double‐edged behavior. The present review offers a detailed overview of the pathways and metabolic routes that can be modulated to halt and redirect their fibro/adipogenic potential while favoring their supportive role in muscle regeneration. Finally, we discuss on how single‐cell technologies have contributed to resolve FAP transitional states with distinctive roles in muscle regeneration and myopathies.

Degradation of the endoplasmic reticulum (ER) via selective autophagy (ER-phagy) is vital for cellular homeostasis. We identify FAM134A/RETREG2 and FAM134C/RETREG3 as ER-phagy receptors, which predominantly exist in an inactive state under basal conditions. Upon autophagy induction and ER stress signal, they can induce significant ER fragmentation and subsequent lysosomal degradation. FAM134A, FAM134B/RETREG1, and FAM134C are essential for maintaining ER morphology in a LC3-interacting region (LIR)-dependent manner. Overexpression of any FAM134 paralogue has the capacity to significantly augment the general ER-phagy flux upon starvation or ER-stress. Global proteomic analysis of FAM134 overexpressing and knockout cell lines reveals several protein clusters that are distinctly regulated by each of the FAM134 paralogues as well as a cluster of commonly regulated ER-resident proteins. Utilizing pro-Collagen I, as a shared ER-phagy substrate, we observe that FAM134A acts in a LIR-independent manner and compensates for the loss of FAM134B and FAM134C, respectively. FAM134C instead is unable to compensate for the loss of its paralogues. Taken together, our data show that FAM134 paralogues contribute to common and unique ER-phagy pathways.

Fibro-adipogenic progenitors (FAPs) promote satellite cell differentiation in adult skeletal muscle regeneration. However, in pathological conditions, FAPs are responsible for fibrosis and fatty infiltrations. Here we show that the NOTCH pathway negatively modulates FAP differentiation both in vitro and in vivo. However, FAPs isolated from young dystrophin-deficient mdx mice are insensitive to this control mechanism. An unbiased mass spectrometry–based proteomic analysis of FAPs from muscles of wild-type and mdx mice suggested that the synergistic cooperation between NOTCH and inflammatory signals controls FAP differentiation. Remarkably, we demonstrated that factors released by hematopoietic cells restore the sensitivity to NOTCH adipogenic inhibition in mdx FAPs. These results offer a basis for rationalizing pathological ectopic fat infiltrations in skeletal muscle and may suggest new therapeutic strategies to mitigate the detrimental effects of fat depositions in muscles of dystrophic patients.

SPP1+ macrophages, characterized by elevated expression of the osteopontin gene (secreted phosphoprotein 1, SPP1), have emerged as key players in various pathological contexts, including aging, chronic inflammatory diseases, and cancer. While frequently classified as a subclass of tumor‐associated macrophages in oncological settings, their presence in noncancer conditions, such as aging‐related disorders and muscular diseases, suggests a broader role beyond tumors. These macrophages share conserved traits, including fibrosis promotion, extracellular matrix remodeling, and immune modulation, often linked to poor clinical outcomes. This perspective explores the multifaceted roles of SPP1+ macrophages across diseases and advocates for their reclassification as a distinct macrophage subtype associated with chronic or prolonged inflammation. Recognizing their cross‐disease relevance could reshape macrophage biology and inform targeted therapeutic strategies.