Skeletal muscle has remarkable regeneration capabilities, mainly due to its resident muscle stem cells (MuSCs). In this review, we introduce recently developed technologies and the mechanistic insights they provide to the understanding of MuSC biology, including the re-definition of quiescence and Galert states. Additionally, we present recent studies that link MuSC function with cellular heterogeneity, highlighting the complex regulation of self-renewal in regeneration, muscle disorders and aging. Finally, we discuss MuSC metabolism and its role, as well as the multifaceted regulation of MuSCs by their niche. The presented conceptual advances in the MuSC field impact on our general understanding of stem cells and their therapeutic use in regenerative medicine.

BackgroundDental pulp represents an easily accessible autologous source of adult stem cells. A subset of these cells, named dental pulp pluripotent-like stem cells (DPPSC), shows high plasticity and can undergo multiple population doublings, making DPPSC an appealing tool for tissue repair or maintenance.MethodsDPPSC were harvested from the dental pulp of third molars extracted from young patients. Growth factors released by DPPSC were analysed using antibody arrays. Cells were cultured in specific differentiation media and their endothelial, smooth and skeletal muscle differentiation potential was evaluated. The therapeutic potential of DPPSC was tested in a wound healing mouse model and in two genetic mouse models of muscular dystrophy (Scid/mdx and Sgcb-null Rag2-null γc-null).ResultsDPPSC secreted several growth factors involved in angiogenesis and extracellular matrix deposition and improved vascularisation in all three murine models. Moreover, DPPSC stimulated re-epithelialisation and ameliorated collagen deposition and organisation in healing wounds. In dystrophic mice, DPPSC engrafted in the skeletal muscle of both dystrophic murine models and showed integration in muscular fibres and vessels. In addition, DPPSC treatment resulted in reduced fibrosis and collagen content, larger cross-sectional area of type II fast-glycolytic fibres and infiltration of higher numbers of proangiogenic CD206+ macrophages.ConclusionsOverall, DPPSC represent a potential source of stem cells to enhance the wound healing process and slow down dystrophic muscle degeneration.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0621-3) contains supplementary material, which is available to authorized users.

Please cite this article as: Rotini Alessio, Martínez-Sarrà Ester, Pozzo Enrico, Sampaolesi Maurilio.Interactions between microRNAs and long noncoding RNAs in cardiac development and repair.Pharmacological Research http://dx.doi.org/10.1016/j.phrs. 2017.05.029 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Graphical abstract.The regulation of cardiac development by miRs and lncRNAs, and their interaction in pathological setting. AbstractNon-coding RNAs (ncRNAs) are emerging players in muscle regulation. Based on their length and differences in molecular structure, ncRNAs are subdivided into several categories including small interfering RNAs, stable non-coding RNAs, microRNAs (miRs), long non-coding RNAs (lncRNAs), and circular RNAs. miRs and lncRNAs are able to post-transcriptionally regulate many genes and bring into play several traits simultaneously due to a myriad of different targets. Recent studies have emphasized their importance in cardiac regeneration and repair. As their altered expression affects 3 cardiac function, miRs and lncRNAs could be potential targets for therapeutic intervention. In this context, miR-and lncRNA-based gene therapies are an interesting field for harnessing the complexity of ncRNA-based therapeutic approaches in cardiac diseases. In this review we will focus on lncRNA-and miR-driven regulations of cardiac development and repair. Finally, we will summarize miRs and lncRNAs as promising candidates for the treatment of heart diseases.

Purpose: The aim of this study was to determine whether 12 days of low-to-moderate exercise training at low altitude (598 m a.s.l.) improves skeletal muscle regeneration in sedentary adult women.Methods: Satellite cells were obtained from the vastus lateralis skeletal muscle of seven women before and after this exercise training at low altitude. They were investigated for differentiation aspects, superoxide anion production, antioxidant enzymes, mitochondrial potential variation after a depolarizing insult, intracellular Ca 2+ concentrations, and micro (mi)RNA expression (miR-1, miR-133, miR-206).Results: In these myogenic populations of adult stem cells, those obtained after exercise training, showed increased Fusion Index and intracellular Ca 2+ concentrations. This exercise training also generally reduced superoxide anion production in cells (by 12-67%), although not in two women, where there was an increase of ∼15% along with a reduced superoxide dismutase activity. miRNA expression showed an exercise-induced epigenetic transcription profile that was specific according to the reduced or increased superoxide anion production of the cells.Conclusions: The present study shows that low-to-moderate exercise training at low altitude improves the regenerative capacity of skeletal muscle in adult women. The differentiation of cells was favored by increased intracellular calcium concentration and increased the fusion index. This low-to-moderate training at low altitude also depicted the epigenetic signature of cells.

Denervation leads to the activation of the catabolic pathways, such as the ubiquitin-proteasome and autophagy, resulting in skeletal muscle atrophy and weakness. Furthermore, denervation induces oxidative stress in skeletal muscle, which is thought to contribute to the induction of skeletal muscle atrophy. Several muscle diseases are characterized by denervation, but the molecular pathways contributing to muscle atrophy have been only partially described. Our study delineates the kinetics of activation of oxidative stress response in skeletal muscle following denervation. Despite the denervation-dependent induction of oxidative stress in skeletal muscle, treatments with anti-oxidant drugs do not prevent the reduction of muscle mass. Our results indicate that, although oxidative stress may contribute to the activation of the response to denervation, it is not responsible by itself of oxidative damage or neurogenic muscle atrophy.

SummarySarcopenia is the age‐related loss of muscle mass, strength, and function. Although the role of human satellite cells (SCs) as adult skeletal muscle stem cells has been deeply investigated, little is known about the impact of aging on muscle interstitial stem cells. Here, we isolated the non‐SC CD56– fraction from human muscle biopsies of young and elderly subjects. The elderly interstitial cell population contained a higher number of CD15+ and PDGFRα+ cells when compared to young samples. In addition, we found that the CD56–/ALP + cells were well represented as a multipotent stem cell population inside the CD56– fraction. CD56–/ALP +/CD15– cells were clonogenic, and since they were myogenic and expressed NG2, α‐SMA and PDGFRβ can be considered mesoangioblasts (MABs). Interestingly, elderly MABs displayed a dramatic impairment in the myogenic differentiation ability in vitro and when transplanted in dystrophic immunodeficient Sgcb‐null Rag2‐null γc‐null mice. In addition, elderly MABs proliferated less, but yet retained other multilineage capabilities. Overall, our results indicate that aging negatively impacted on the regenerative potential of MABs and this should be carefully considered for potential therapeutic applications of MABs.

Recent studies have revealed the contribution of fibro-adipogenic progenitors (FAPs) to the pathogenesis and progression of Duchenne Muscular Dystrophy (DMD). While FAPs direct compensatory regeneration at early stages of disease, as the disease progresses they contribute to the progressive replacement of contractile myofibers with fibrotic scars and fatty infiltration. Using the mouse model of DMD – the mdx mice - we have recently reported that FAPs mediate the ability of HDAC inhibitors (HDACi) to promote muscle regeneration and prevent fibro-adipogenic degeneration at early stages of disease. This effect is mediated by the induction of myomiRs that, in turn, target the SWI/SNF components BAF60A and B, thereby favoring the formation of BAF60C-based SWI/SNF complex, which directs the switch from the fibro-adipogenic to the myogenic lineage. Here we show direct evidence of induction of miR-206 and BAF60C, and reduction of BAF60A, in FAPs isolated from mdx muscles exposed to the HDACi Trichostatin A (TSA). We also discuss how increased expression of myomiRs in dystrophic muscles can be integrated with circulating myomiRs to provide accurate biomarkers of disease progression and response to treatment.

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