Mammalian cells exhibit remarkable diversity in cell size, but the factors that regulate establishment and maintenance of these sizes remain poorly understood. This is especially true for skeletal ...muscle, comprised of syncytial myofibers that each accrue hundreds of nuclei during development. Here, we directly explore the assumed causal relationship between multinucleation and establishment of normal size through titration of myonuclear numbers during mouse neonatal development. Three independent mouse models, where myonuclear numbers were reduced by 75, 55, or 25%, led to the discovery that myonuclei possess a reserve capacity to support larger functional cytoplasmic volumes in developing myofibers. Surprisingly, the results revealed an inverse relationship between nuclei numbers and reserve capacity. We propose that as myonuclear numbers increase, the range of transcriptional return on a per nuclear basis in myofibers diminishes, which accounts for both the absolute reliance developing myofibers have on nuclear accrual to establish size, and the limits of adaptability in adult skeletal muscle.
Skeletal muscle contains a designated population of adult stem cells, called satellite cells, which are generally quiescent. In homeostasis, satellite cells proliferate only sporadically and usually ...by asymmetric cell division to replace myofibres damaged by daily activity and maintain the stem cell pool. However, satellite cells can also be robustly activated upon tissue injury, after which they undergo symmetric divisions to generate new stem cells and numerous proliferating myoblasts that later differentiate to muscle cells (myocytes) to rebuild the muscle fibre, thereby supporting skeletal muscle regeneration. Recent discoveries show that satellite cells have a great degree of population heterogeneity, and that their cell fate choices during the regeneration process are dictated by both intrinsic and extrinsic mechanisms. Extrinsic cues come largely from communication with the numerous distinct stromal cell types in their niche, creating a dynamically interactive microenvironment. This Review discusses the role and regulation of satellite cells in skeletal muscle homeostasis and regeneration. In particular, we highlight the cell-intrinsic control of quiescence versus activation, the importance of satellite cell-niche communication, and deregulation of these mechanisms associated with ageing. The increasing understanding of how satellite cells are regulated will help to advance muscle regeneration and rejuvenation therapies.
•Skeletal muscle gauge was recently introduced as an imaging indicator of sarcopenia; however, the use of skeletal muscle gauge is limited to patients who undergo computed tomography.•A machine ...learning algorithm using clinical and inflammatory markers to predict skeletal muscle gauge in patients with colorectal cancer was developed with better predictive power.•This machine learning model can be used as a screening tool to detect sarcopenic status without using computed tomography during the treatment period.
Skeletal muscle gauge (SMG) was recently introduced as an imaging indicator of sarcopenia. Computed tomography is essential for measuring SMG; thus, the use of SMG is limited to patients who undergo computed tomography. We aimed to develop a machine learning algorithm using clinical and inflammatory markers to predict SMG in patients with colorectal cancer.
The least absolute shrinkage and selection operator regression model was applied for variable selection and predictive signature building in the training set. The predictive accuracy of the least absolute shrinkage and selection operator model, defined as linear predictor (LP)-SMG, was compared using the area under the receiver operating characteristic curve and decision curve analysis in the test set.
A total of 1094 patients with colorectal cancer were enrolled and randomly categorized into training (n = 656) and test (n = 438) sets. Low SMG was identified in 142 (21.6%) and 90 (20.5%) patients in the training and test sets, respectively. According to multivariable analysis of the test sets, LP-SMG was identified as an independent predictor of low SMG (odds ratio = 1329.431; 95% CI, 271.684–7667.996; P < .001). Its predictive performance was similar in the training and test sets (area under the receiver operating characteristic curve = 0.846 versus 0.869; P = .427). In the test set, LP-SMG had better outcomes in predicting SMG than single clinical variables, such as sex, height, weight, and hemoglobin.
LP-SMG had superior performance than single variables in predicting low SMG. This machine learning model can be used as a screening tool to detect sarcopenic status without using computed tomography during the treatment period.
Lipid droplets (LD) play a central role in lipid homeostasis by controlling transient fatty acid (FA) storage and release from triacylglycerols stores, while preventing high levels of cellular toxic ...lipids. This crucial function in oxidative tissues is altered in obesity and type 2 diabetes. Perilipin 5 (PLIN5) is a LD protein whose mechanistic and causal link with lipotoxicity and insulin resistance has raised controversies. We investigated here the physiological role of PLIN5 in skeletal muscle upon various metabolic challenges. We show that PLIN5 protein is elevated in endurance-trained (ET) subjects and correlates with muscle oxidative capacity and whole-body insulin sensitivity. When overexpressed in human skeletal muscle cells to recapitulate the ET phenotype, PLIN5 diminishes lipolysis and FA oxidation under basal condition, but paradoxically enhances FA oxidation during forskolin- and contraction- mediated lipolysis. Moreover, PLIN5 partly protects muscle cells against lipid-induced lipotoxicity. In addition, we demonstrate that down-regulation of PLIN5 in skeletal muscle inhibits insulin-mediated glucose uptake under normal chow feeding condition, while paradoxically improving insulin sensitivity upon high-fat feeding. These data highlight a key role of PLIN5 in LD function, first by finely adjusting LD FA supply to mitochondrial oxidation, and second acting as a protective factor against lipotoxicity in skeletal muscle.
A longstanding goal in regenerative medicine is to reconstitute functional tissues or organs after injury or disease. Attention has focused on the identification and relative contribution of tissue ...specific stem cells to the regeneration process. Relatively little is known about how the physiological process is regulated by other tissue constituents. Numerous injury models are used to investigate tissue regeneration, however, these models are often poorly understood. Specifically, for skeletal muscle regeneration several models are reported in the literature, yet the relative impact on muscle physiology and the distinct cells types have not been extensively characterised.
We have used transgenic Tg:Pax7nGFP and Flk1GFP/+ mouse models to respectively count the number of muscle stem (satellite) cells (SC) and number/shape of vessels by confocal microscopy. We performed histological and immunostainings to assess the differences in the key regeneration steps. Infiltration of immune cells, chemokines and cytokines production was assessed in vivo by Luminex®.
We compared the 4 most commonly used injury models i.e. freeze injury (FI), barium chloride (BaCl2), notexin (NTX) and cardiotoxin (CTX). The FI was the most damaging. In this model, up to 96% of the SCs are destroyed with their surrounding environment (basal lamina and vasculature) leaving a "dead zone" devoid of viable cells. The regeneration process itself is fulfilled in all 4 models with virtually no fibrosis 28 days post-injury, except in the FI model. Inflammatory cells return to basal levels in the CTX, BaCl2 but still significantly high 1-month post-injury in the FI and NTX models. Interestingly the number of SC returned to normal only in the FI, 1-month post-injury, with SCs that are still cycling up to 3-months after the induction of the injury in the other models.
Our studies show that the nature of the injury model should be chosen carefully depending on the experimental design and desired outcome. Although in all models the muscle regenerates completely, the trajectories of the regenerative process vary considerably. Furthermore, we show that histological parameters are not wholly sufficient to declare that regeneration is complete as molecular alterations (e.g. cycling SCs, cytokines) could have a major persistent impact.
The progressive loss of muscle regenerative capacity with age or disease results in part from a decline in the number and function of satellite cells, the direct cellular contributors to muscle ...repair. However, little is known about the molecular effectors underlying satellite cell impairment and depletion. Elevated levels of inflammatory cytokines, including interleukin-6 (IL-6), are associated with both age-related and muscle-wasting conditions. The levels of STAT3, a downstream effector of IL-6, are also elevated with muscle wasting, and STAT3 has been implicated in the regulation of self-renewal and stem cell fate in several tissues. Here we show that IL-6-activated Stat3 signaling regulates satellite cell behavior, promoting myogenic lineage progression through myogenic differentiation 1 (Myod1) regulation. Conditional ablation of Stat3 in Pax7-expressing satellite cells resulted in their increased expansion during regeneration, but compromised myogenic differentiation prevented the contribution of these cells to regenerating myofibers. In contrast, transient Stat3 inhibition promoted satellite cell expansion and enhanced tissue repair in both aged and dystrophic muscle. The effects of STAT3 inhibition on cell fate and proliferation were conserved in human myoblasts. The results of this study indicate that pharmacological manipulation of STAT3 activity can be used to counteract the functional exhaustion of satellite cells in pathological conditions, thereby maintaining the endogenous regenerative response and ameliorating muscle-wasting diseases.
Inflammation is usually considered as harmful; however, it is also necessary for tissue recovery after injury. Macrophages exert immune and nonimmune functions throughout this process. During ...skeletal muscle regeneration, they mount an inflammatory response while exerting trophic roles on muscle and mesenchymal stem cells. Proinflammatory macrophages shift to being anti-inflammatory, triggering the resolution of inflammation. Studies have highlighted that during this shift, a crosstalk ensues, integrating cues for resolution, efferocytosis, cellular metabolism, and signaling pathways. During the restorative phase, macrophages dampen inflammation while promoting stem cell differentiation, angiogenesis, and matrix remodeling. Since blunting the inflammatory phase can be detrimental for muscle regeneration, we suggest that rather than fighting inflammation, it should be allowed to operate and resolve, thus allowing for tissue recovery.
Macrophages are key orchestrators of the inflammatory response after tissue injury. They do so by controlling both proinflammatory and restorative/anti-inflammatory phases, and by sequentially exerting a variety of functions impacting on parenchymal, vascular, and fibroblastic cells.The resolution of inflammation is mandatory for tissue repair and consists of shifting the inflammatory status of macrophages from a pro- towards an anti-inflammatory/restorative profile. It is mainly operated by macrophages through efferocytosis, that is, phagocytosis of dead cells and debris.The shift occurring in macrophage inflammatory status and the resolution of inflammation are controlled by integrating early inflammation-resolving cues, efferocytosis, rewiring of cellular metabolism, and activation of specific intracellular signaling pathways.We posit that while the proinflammatory phase is shorter and less intense after tissue injury than during a given infection, this natural response should not be blunted. In injured skeletal muscle, applying an anti-inflammatory treatment too early can be detrimental in returning to homeostasis.
Skeletal muscle development and fat deposition have important effects on meat quality. The study of regulating skeletal muscle development and fat deposition is of great significance in improving the ...quality of carcass and meat. In the present study, whole transcriptome sequencing (including RNA-Seq and miRNA-Seq) was performed on the longissimus dorsi muscle (LDM) of Jinfen White pigs at 1, 90, and 180 days of age.
The results showed that a total of 245 differentially expressed miRNAs were screened in any two comparisons, which may be involved in the regulation of myogenesis. Among them, compared with 1-day-old group, miR-22-5p was significantly up-regulated in 90-day-old group and 180-day-old group. Functional studies demonstrated that miR-22-5p inhibited the proliferation and differentiation of porcine skeletal muscle satellite cells (PSCs). Pearson correlation coefficient analysis showed that long non-coding RNA (lncRNA) LOC106505926 and CXXC5 gene had strong negative correlations with miR-22-5p. The LOC106505926 and CXXC5 were proven to promote the proliferation and differentiation of PSCs, as opposed to miR-22-5p. In terms of mechanism, LOC106505926 functions as a molecular sponge of miR-22-5p to modulate the expression of CXXC5, thereby inhibits the differentiation of PSCs. In addition, LOC106505926 regulates the differentiation of porcine preadipocytes through direct binding with FASN.
Collectively, our results highlight the multifaceted regulatory role of LOC106505926 in controlling skeletal muscle and adipose tissue development in pigs and provide new targets for improving the quality of livestock products by regulating skeletal muscle development and fat deposition.
Older men (n = 12) and women (n = 18) 65-80 years of age completed 12 weeks of exercise and took either a placebo or resveratrol (RSV) (500 mg/d) to test the hypothesis that RSV treatment combined ...with exercise would increase mitochondrial density, muscle fatigue resistance, and cardiovascular function more than exercise alone. Contrary to our hypothesis, aerobic and resistance exercise coupled with RSV treatment did not reduce cardiovascular risk further than exercise alone. However, exercise added to RSV treatment improved the indices of mitochondrial density, and muscle fatigue resistance more than placebo and exercise treatments. In addition, subjects that were treated with RSV had an increase in knee extensor muscle peak torque (8%), average peak torque (14%), and power (14%) after training, whereas exercise did not increase these parameters in the placebo-treated older subjects. Furthermore, exercise combined with RSV significantly improved mean fiber area and total myonuclei by 45.3% and 20%, respectively, in muscle fibers from the vastus lateralis of older subjects. Together, these data indicate a novel anabolic role of RSV in exercise-induced adaptations of older persons and this suggests that RSV combined with exercise might provide a better approach for reversing sarcopenia than exercise alone.
The proper functioning of tissues and organs depends on their ability to self-renew and repair. Some of the tissues, like epithelia, renew almost constantly while in the others this process is ...induced by injury or diseases. The stem or progenitor cells responsible for tissue homeostasis have been identified in many organs. Some of them, such as hematopoietic or intestinal epithelium stem cells, are multipotent and can differentiate into various cell types. Others are unipotent. The skeletal muscle tissue does not self-renew spontaneously, however, it presents unique ability to regenerate in response to the injury or disease. Its repair almost exclusively relies on unipotent satellite cells. However, multiple lines of evidence document that some progenitor cells present in the muscle can be supportive for skeletal muscle regeneration. Here, we summarize the current knowledge on the complicated landscape of stem and progenitor cells that exist in skeletal muscle and support its regeneration. We compare the cells from two model organisms, i.e., mouse and human, documenting their similarities and differences and indicating methods to test their ability to undergo myogenic differentiation.
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