Chronic inflammation impairs skeletal muscle regeneration. Although many cells are involved in chronic inflammation, macrophages seem to play an important role in impaired muscle regeneration since these cells are associated with skeletal muscle stem cell (namely, satellite cells) activation and fibro-adipogenic progenitor cell (FAP) survival. Specifically, an imbalance of M1 and M2 macrophages seems to lead to impaired satellite cell activation, and these are the main cells that function during skeletal muscle regeneration, after muscle damage. Additionally, this imbalance leads to the accumulation of FAPs in skeletal muscle, with aberrant production of pro-fibrotic factors (e.g., extracellular matrix components), impairing the niche for proper satellite cell activation and differentiation. Treatments aiming to block the inflammatory pro-fibrotic response are partially effective due to their side effects. Therefore, strategies reverting chronic inflammation into a pro-regenerative pattern are required. In this review, we first describe skeletal muscle resident macrophage ontogeny and homeostasis, and explain how macrophages are replenished after muscle injury. We next discuss the potential role of chronic physical activity and exercise in restoring the M1 and M2 macrophage balance and consequently, the satellite cell niche to improve skeletal muscle regeneration after injury.

Introduction: Reduction in skeletal muscle regeneration capacity, such as in inflammatory muscle diseases and aging, leads to progressive muscle strength decrement, which impairs mobility and increases risk of falls and mortality, with a negative impact of quality of life. This reduction in skeletal muscle regeneration has been associated with an impaired function of the skeletal muscle stem cells, namely, the satellite cells. These cells are localized beneath basal lamina in a quiescence state and can be activated and differentiated into new myofibers after muscle damage. Indeed, satellite cells need to exit the cell cycle for differentiation. Therefore, the search for biological tools that can improve activation/differentiation of satellite cells is of great interest to regenerative medicine. In this regard, butyrate, a gut microbial metabolite, which can induce cell cycle arrest through histone deacetylase inhibition, has emerged as a therapeutic tool in some diseases, such as cancer. Then, we hypothesize that butyrate could improve skeletal muscle regeneration by accelerating satellite cellsdifferentiation into myofibers through epigenetics mechanisms related to cell cycle exit. Objectives: To assess whether butyrate could improve skeletal muscle regeneration after barium chloride damage and its epigenetics mechanisms. Methods: Twenty C57Bl/6 male mice (CEUA: 133/2014), with 8 weeks of age, were grouped as follows: (1) control group with no injury + saline (C-Sal); (2) control group with no injury + butyrate (CBut); (3) injury with saline (I-Sal);and (4) injury + butyrate (I-But). The muscle injury was performed with the injection of 50 μL of barium chloride (1.2%) in both tibialis anterior and the muscles were harvested six and twelve days after injury for histological and molecular analyses. Butyrate were injected intraperitoneally (400 mg/kg) for 6 days. For in vitro assays, primary satellite cells were isolated and cultured as myoblasts. Myoblasts were treated with 300 μM of butyrate during proliferation and differentiation conditions in order to assess cell cycle molecules, differentiation index, and epigenetics mechanisms. The significance was assumed when P < 0.05. Results: Skeletal muscle regeneration, assessed by cross-sectional area of tibialis anterior muscle, was higher in I-But than I-Sal group (P < 0.05). Histogram analysis also showed higher frequency of smaller fibers in I-Sal than I-But group (P < 0.05). In vitro analyses showed a reduction in the myoblasts proliferation when treated with butyrate (P < 0.05). Also, butyrate treatment downregulated genes related to cell cycle activation (cdk1, cdk2, cdk4), and up-regulated genes related to cell cycle repression (p57) (P < 0.05). The myotubes differentiation, assessed by fusion index, were higher in myoblasts treated with butyrate (P < 0.05), which was followed by an upregulation of the myogenic marker of differentiation, myogenin (P < 0.05). Moreover, butyrate was able to decrease histone deacetylase (P < 0.05) and increase histone acetyltransferase enzymatic activities (P < 0.05). Conclusion and discussion: Butyrate increased skeletal muscle regeneration in mice by accelerating the myotubes differentiation through induction of cell cycle arrest in myoblasts. Preliminary data suggested that this improvement was epigenetically mediated.

A obesidade está intimamente ligada ao estado inflamatório, sendo considerada uma patologia metabólica complexa. Dietas hipercalóricas alteram a composição da microbiota intestinal, sendo a mudança da proporção de bactérias dos filos Bacteroidetes e Firmicutes uma das consequências mais conhecidas.  Essa mudança determina a produção de metabólitos específicos do sistema imune, induzindo estado inflamatório responsável pelo agravamento de uma série de doenças. A dieta hipercalórica representa um fator de risco para a obesidade e para o diabetes mellitus, doenças interligadas pelo conceito de lipotoxicidade, e o estado inflamatório também contribui para o aparecimento e para a progressão de doenças cardiovasculares. Com esse artigo, objetivamos estudar a obesidade pela perspectiva imunológica e microbiológica, abordando as consequências de dietas hipercalóricas sobre o estado inflamatório e a sobre a microbiota. Ademais, associar a mudança no microbioma a doenças prevalentes como o diabetes mellitus e as doenças cardiovasculares, apontando abordagens terapêuticas potenciais.