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.

The War after War: Volumetric Muscle Loss Incidence, Implication, Current Therapies and Emerging Reconstructive Strategies, a Comprehensive Review.

Volumetric muscle loss (VML) is the massive wasting of skeletal muscle tissue due to traumatic events or surgical ablation. This pathological condition exceeds the physiological healing process carried out by the muscle itself, which owns remarkable capacity to restore damages but only when limited in dimensions. Upon VML occurring, the affected area is severely compromised, heavily influencing the affected a person's quality of life. Overall, this condition is often associated with chronic disability, which makes the return to duty of highly specialized professional figures (e.g., military personnel or athletes) almost impossible. The actual treatment for VML is based on surgical conservative treatment followed by physical exercise; nevertheless, the results, in terms of either lost mass and/or functionality recovery, are still poor. On the other hand, the efforts of the scientific community are focusing on reconstructive therapy aiming at muscular tissue void volume replenishment by exploiting biomimetic matrix or artificial tissue implantation. Reconstructing strategies represent a valid option to build new muscular tissue not only to recover damaged muscles, but also to better socket prosthesis in terms of anchorage surfaces and reinnervation substrates for reconstructed mass.

Muscle Diversity, Heterogeneity, and Gradients: Learning from Sarcoglycanopathies.

Skeletal muscle, the most abundant tissue in the body, is heterogeneous. This heterogeneity forms the basis of muscle diversity, which is reflected in the specialized functions of muscles in different parts of the body. However, these different parts are not always clearly delimitated, and this often gives rise to gradients within the same muscle and even across the body. During the last decade, several studies on muscular disorders both in mice and in humans have observed particular distribution patterns of muscle weakness during disease, indicating that the same mutation can affect muscles differently. Moreover, these phenotypical differences reveal gradients of severity, existing alongside other architectural gradients. These two factors are especially prominent in sarcoglycanopathies. Nevertheless, very little is known about the mechanism(s) driving the phenotypic diversity of the muscles affected by these diseases. Here, we will review the available literature on sarcoglycanopathies, focusing on phenotypic differences among affected muscles and gradients, characterization techniques, molecular signatures, and cell population heterogeneity, highlighting the possibilities opened up by new technologies. This review aims to revive research interest in the diverse disease phenotype affecting different muscles, in order to pave the way for new therapeutic interventions.

Biofabricating murine and human myo-substitutes for rapid volumetric muscle loss restoration.

The importance of skeletal muscle tissue is undoubted being the controller of several vital functions including respiration and all voluntary locomotion activities. However, its regenerative capability is limited and significant tissue loss often leads to a chronic pathologic condition known as volumetric muscle loss. Here, we propose a biofabrication approach to rapidly restore skeletal muscle mass, 3D histoarchitecture, and functionality. By recapitulating muscle anisotropic organization at the microscale level, we demonstrate to efficiently guide cell differentiation and myobundle formation both in vitro and in vivo. Of note, upon implantation, the biofabricated myo-substitutes support the formation of new blood vessels and neuromuscular junctions-pivotal aspects for cell survival and muscle contractile functionalities-together with an advanced muscle mass and force recovery. Altogether, these data represent a solid base for further testing the myo-substitutes in large animal size and a promising platform to be eventually translated into clinical scenarios.

Platelet-Derived Growth Factor BB Influences Muscle Regeneration in Duchenne Muscle Dystrophy.

Duchenne muscular dystrophy (DMD) is characterized by a progressive loss of muscle fibers, and their substitution by fibrotic and adipose tissue. Many factors contribute to this process, but the molecular pathways related to regeneration and degeneration of muscle are not completely known. Platelet-derived growth factor (PDGF)-BB belongs to a family of growth factors that regulate proliferation, migration, and differentiation of mesenchymal cells. The role of PDGF-BB in muscle regeneration in humans has not been studied. We analyzed the expression of PDGF-BB in muscle biopsy samples from controls and patients with DMD. We performed in vitro experiments to understand the effects of PDGF-BB on myoblasts involved in the pathophysiology of muscular dystrophies and confirmed our results in vivo by treating the mdx murine model of DMD with repeated i.m. injections of PDGF-BB. We observed that regenerating and necrotic muscle fibers in muscle biopsy samples from DMD patients expressed PDGF-BB. In vitro, PDGF-BB attracted myoblasts and activated their proliferation. Analysis of muscles from the animals treated with PDGF-BB showed an increased population of satellite cells and an increase in the number of regenerative fibers, with a reduction in inflammatory infiltrates, compared with those in vehicle-treated mice. Based on our results, PDGF-BB may play a protective role in muscular dystrophies by enhancing muscle regeneration through activation of satellite cell proliferation and migration.