Sex differences in inflammation and muscle wasting in aging and disease

: Only in recent years, thanks to a precision medicine-based approach, have treatments tailored to the sex of each patient emerged in clinical trials. In this regard, both striated muscle tissues present significant differences between the two sexes, which may have important consequences for diagnosis and therapy in aging and chronic illness. In fact, preservation of muscle mass in disease conditions correlates with survival; however, sex should be considered when protocols for the maintenance of muscle mass are designed. One obvious difference is that men have more muscle than women. Moreover, the two sexes differ in inflammation parameters, particularly in response to infection and disease. Therefore, unsurprisingly, men and women respond differently to therapies. In this review, we present an up-to-date overview on what is known about sex differences in skeletal muscle physiology and disfunction, such as disuse atrophy, age-related sarcopenia, and cachexia. In addition, we summarize sex differences in inflammation which may underly the aforementioned conditions because pro-inflammatory cytokines deeply affect muscle homeostasis. The comparison of these three conditions and their sex-related bases is interesting because different forms of muscle atrophy share common mechanisms; for instance, those responsible for protein dismantling are similar although differing in terms of kinetics, severity, and regulatory mechanisms. In pre-clinical research, exploring sexual dimorphism in disease conditions could highlight new efficacious treatments or recommend implementation of an existing one. Any protective factors discovered in one sex could be exploited to achieve lower morbidity, reduce the severity of the disease, or avoid mortality in the opposite sex. Thus, the understanding of sex-dependent responses to different forms of muscle atrophy and inflammation is of pivotal importance to design innovative, tailored, and efficient interventions

Spatially resolved transcriptomics reveals innervation-responsive functional clusters in skeletal muscle

Striated muscle is a highly organized structure composed of well-defined anatomical domains with integrated but distinct assignments. So far, the lack of a direct correlation between tissue architecture and gene expression has limited our understanding of how each unit responds to physio-pathologic contexts. Here, we show how the combined use of spatially resolved transcriptomics and immunofluorescence can bridge this gap by enabling the unbiased identification of such domains and the characterization of their response to external perturbations. Using a spatiotemporal analysis, we follow changes in the transcriptome of specific domains in muscle in a model of denervation. Furthermore, our approach enables us to identify the spatial distribution and nerve dependence of atrophic signaling pathway and polyamine metabolism to glycolytic fibers. Indeed, we demonstrate that perturbations of polyamine pathway can affect muscle function. Our dataset serves as a resource for future studies of the mechanisms underlying skeletal muscle homeostasis and innervation

Rate and duration of hospitalisation for acute pulmonary embolism in the real-world clinical practice of different countries : Analysis from the RIETE registry

publishersversionPeer reviewe

Injury-experienced satellite cells retain long-term enhanced regenerative capacity

Abstract Background Inflammatory memory or trained immunity is a recently described process in immune and non-immune tissue resident cells, whereby previous exposure to inflammation mediators leads to a faster and stronger responses upon secondary challenge. Whether previous muscle injury is associated with altered responses to subsequent injury by satellite cells (SCs), the muscle stem cells, is not known. Methods We used a mouse model of repeated muscle injury, in which intramuscular cardiotoxin (CTX) injections were administered 50 days apart in order to allow for full recovery of the injured muscle before the second injury. The effect of prior injury on the phenotype, proliferation and regenerative potential of satellite cells following a second injury was examined in vitro and in vivo by immunohistochemistry, RT-qPCR and histological analysis. Results We show that SCs isolated from muscle at 50 days post-injury (injury-experienced SCs (ieSCs)) enter the cell cycle faster and form bigger myotubes when cultured in vitro, compared to control SCs isolated from uninjured contralateral muscle. Injury-experienced SCs were characterized by the activation of the mTORC 1 signaling pathway, suggesting they are poised to activate sooner following a second injury. Consequently, upon second injury, SCs accumulate in greater numbers in muscle at 3 and 10 days after injury. These changes in SC phenotype and behavior were associated with accelerated muscle regeneration, as evidenced by an earlier appearance of bigger fibers and increased number of myonuclei per fiber at day 10 after the second injury. Conclusions Overall, we show that skeletal muscle injury has a lasting effect on SC function priming them to respond faster to a subsequent injury. The ieSCs have long-term enhanced regenerative properties that contribute to accelerated regeneration following a secondary challenge

Additional file 6 of Injury-experienced satellite cells retain long-term enhanced regenerative capacity

Additional file 6: Fig. S6: A) Representative images of CD90 staining of FAPs in tibialis anterior 7 days after single or repeated injury. B) Quantification of CD90+ cells per FOV, n = 5 independent samples. C) Representative images of CD68+ macrophages staining of tibialis anterior 10 days after single or repeated injury. D) Quantification of the number of macrophages per field of view (FOV). n = 3 (SI) and 4 (RI) independent samples

Additional file 2 of Injury-experienced satellite cells retain long-term enhanced regenerative capacity

Additional file 2: Fig. S2: A) Quantification of the number of Pax7+ cells per field of view (FOV) after SCs isolation from injured (50 days post-injury (50DPI)) or uninjured muscle assessed by immunofluorescence. B) Quantification of the percentage of Pax7+/ki-67+ SCs isolated 50 DPI or uninjured muscle assessed as in (A). C) Quantification of cell diameter, expressed in microns, of the SCs isolated 50 DPI or uninjured muscle. n = 3 independent samples. Data are shown as mean ± S.E.M

Additional file 1 of Injury-experienced satellite cells retain long-term enhanced regenerative capacity

Additional file 1: Fig. S1: A) Representative images of uninjured muscle (uninj) and 50 days post-cardiotoxin injury (50 DPI) stained by hematoxylin and eosin (H&E), showing complete fiber regeneration by 50 days after injury. B) Representative images of Pax7 and laminin staining in uninjured muscle or 50 days after cardiotoxin injection. C) Quantification of the number of Pax7+ cells per muscle fiber as in (B). n = 3 independent samples. Data are shown as mean ± S.E.M

Additional file 5 of Injury-experienced satellite cells retain long-term enhanced regenerative capacity

Additional file 5: Fig. S5: A) Representative images of FACS gating strategy for the analysis of immune cells in muscle after single or repeated injury. B) Quantification of the number of hematopoietic (CD45+) cells infiltrating the muscle, 18 h, 3 days and 10 days after cardiotoxin injury, or uninjured muscle, and normalized per gram of tissue. C) Quantification of the number of recently recruited inflammatory monocytes/macrophages (F4/80 + Ly6Chi) and neutrophils (Ly6g+) infiltrating the muscle 3 days after cardiotoxin injury, or uninjured control muscle, normalized per gram of tissue. Data are shown as mean ± S.E.M

Additional file 4 of Injury-experienced satellite cells retain long-term enhanced regenerative capacity

Additional file 4: Fig. S4 A) Schematic diagram of the experimental approach for freeze injury (FI). B) Representative images of Pax7/ki-67 staining of tibialis anterioris muscle sections 10 days after single (FI 1) or repeated freeze injury (FI 2). C-D) Quantification of the number of Pax7+ cells per muscle fiber and quantification of the percentage of Pax7+/ki-67+ SCs in muscle sections, as in (B). E) Representative images of centrally nucleated fibers (CNFs), evidenced by laminin staining, in muscle sections, 10 days after single or repeated freeze injury. F-G) Quantification of the cross-sectional area of the CNFs, expressed in square microns, and quantification of the number of nuclei per CNF, as in (D). F) Quantification of the distribution of CNFs per CSA, expressed in percentage, as in (G). 10 days after single or repeated freeze injury, expressed in percentage. N = 5 independent samples. Data are shown as mean ± S.E.M. * p < 0.05, ** p < 0.01

Additional file 7 of Injury-experienced satellite cells retain long-term enhanced regenerative capacity

Additional file 7. Fig. S7: A) Representative images of CD31/ki-67 staining of endothelial cells in tibialis anterior muscle sections 7 days after single or repeated injury. B) Quantification of the number of CD31+ cells per fiber and the percentage of CD31+/ki67+ cells in muscle sections, as in (B). C) Representative images of CD31 and laminin staining of tibialis anterior muscle sections 30 days after single or repeated injury. D) Quantification of the number of CD31+ cells per fiber, as in (B)