A population of fibro/adipogenic but non-myogenic progenitors located between skeletal muscle fibers was recently discovered. The aim of this study was to determine the extent to which these progenitors differentiate into fully functional adipocytes. The characterization of muscle progenitor-derived adipocytes is a central issue in understanding muscle homeostasis. They are considered as being the cellular origin of intermuscular adipose tissue that develops in several pathophysiological situations. Here fibro/adipogenic progenitors were isolated from a panel of 15 human muscle biopsies on the basis of the specific cell-surface immunophenotype CD15+/PDGFRα+CD56−. This allowed investigations of their differentiation into adipocytes and the cellular functions of terminally differentiated adipocytes. Adipogenic differentiation was found to be regulated by the same effectors as those regulating differentiation of progenitors derived from white subcutaneous adipose tissue. Similarly, basic adipocyte functions, such as triglyceride synthesis and lipolysis occurred at levels similar to those observed with subcutaneous adipose tissue progenitor-derived adipocytes. However, muscle progenitor-derived adipocytes were found to be insensitive to insulin-induced glucose uptake, in association with the impairment of phosphorylation of key insulin-signaling effectors. Our findings indicate that muscle adipogenic progenitors give rise to bona fide white adipocytes that have the unexpected feature of being insulin-resistant.

This study was designed to evaluate the effects of hypokinesia and hypodynamia on cytoskeletal and related protein contents in human skeletal muscles. Twelve proteins: dystrophin and its associated proteins (DGC), dysferlin, talin, vinculin and meta-vinculin, alpha-actinin, desmin, actin, and myosin, were quantitatively analyzed during an 84-day long-term bedrest (LTBR). The preventive or compensatory effects of maximal resistance exercise (MRE) as a countermeasure were evaluated. Most of these proteins are involved in several myopathies, and they play an important role in muscle structure, fiber cohesion, cell integrity maintenance, and force transmission. This is the first comparison of the cytoskeletal protein contents between slow postural soleus (SOL) and mixed poly-functional vastus lateralis (VL) human muscles. Protein contents were higher in VL than in SOL (from 12 to 94%). These differences could be mainly explained by the differential mechanical constraints imposed on the muscles, i.e., cytoskeletal protein contents increase with mechanical constraints. After LTBR, proteins belonging to the DGC, dysferlin, and proteins of the costamere exhibited large increases, higher in SOL (from 67 to 216%) than in VL (from 32 to 142%). Plasma membrane remodeling during muscle atrophy is probably one of the key points for interpreting these modifications, and mechanisms other than those involved in the resistance of the cytoskeleton to mechanical constraints may be implicated (membrane repair). MRE compensates the cytoskeletal changes induced by LTBR in SOL, except for gamma-sarcoglycan (+70%) and dysferlin (+108%). The exercise only partly compensated the DGC changes induced in VL, and, as for SOL, dysferlin remained largely increased (+132%). Moreover, vinculin and metavinculin, which exhibited no significant change in VL after LTBR, were increased with MRE during LTBR, reinforcing the pre-LTBR differences between SOL and VL. This knowledge will contribute to the development of efficient space flight countermeasures and rehabilitation methods in clinical situations where musculoskeletal unloading is a component.

Intramuscular fat deposition represents a negative prognostic factor for several myopathies, metabolic diseases and aging. Fibro-adipogenic progenitors (FAPs) are considered as the main source of intramuscular adipocytes, but the mechanisms controlling their adipogenic potential are still not elucidated in humans. The aim of this study was to explore the regulation of human FAP adipogenesis by macrophages. We found that CD140a-expressing FAPs were located close to CD68 positive macrophages in muscles from patients with Duchenne muscular dystrophy (DMD). This strongly suggests a potential interaction between FAPs and macrophages in vivo. Isolated human primary FAPs were then differentiated in the presence of conditioned media obtained from primary blood monocyte-polarized macrophages. Molecules released by IL-1β-polarized macrophages (M(IL-1β)) drastically reduced FAP adipogenic potential as assessed by decreased cellular lipid accumulation and reduced gene expression of adipogenic markers. This was associated with an increased gene expression of pro-inflammatory cytokines in FAPs. Conversely, factors secreted by IL-4-polarized macrophages (M(IL-4)) enhanced FAP adipogenesis. Finally, the inhibition of FAP adipocyte differentiation by M(IL-1β) macrophages requires the stimulation of Smad2 phosphorylation of FAPs. Our findings identify a novel potential crosstalk between FAPs and M(IL-1β) and M(IL-4) macrophages in the development of adipocyte accumulation in human skeletal muscles.