Transition In Skeletal Muscle Research Articles

Endothelial‐mesenchymal transition in skeletal muscle: Opportunities and challenges from 3D microphysiological systems

AbstractFibrosis is a pathological condition that in the muscular context is linked to primary diseases such as dystrophies, laminopathies, neuromuscular disorders, and volumetric muscle loss following traumas, accidents, and surgeries. Although some basic mechanisms regarding the role of myofibroblasts in the progression of muscle fibrosis have been discovered, our knowledge of the complex cell–cell, and cell–matrix interactions occurring in the fibrotic microenvironment is still rudimentary. Recently, vascular dysfunction has been emerging as a key hallmark of fibrosis through a process called endothelial‐mesenchymal transition (EndoMT). Nevertheless, no effective therapeutic options are currently available for the treatment of muscle fibrosis. This lack is partially due to the absence of advanced in vitro models that can recapitulate the 3D architecture and functionality of a vascularized muscle microenvironment in a human context. These models could be employed for the identification of novel targets and for the screening of potential drugs blocking the progression of the disease. In this review, we explore the potential of 3D human muscle models in studying the role of endothelial cells and EndoMT in muscle fibrotic tissues and identify limitations and opportunities for optimizing the next generation of these microphysiological systems. Starting from the biology of muscle fibrosis and EndoMT, we highlight the synergistic links between different cell populations of the fibrotic microenvironment and how to recapitulate them through microphysiological systems.

Effects of clenbuterol administration on mitochondrial morphology and its regulatory proteins in rat skeletal muscle.

Clenbuterol induces a slow‐to‐fast fiber type transition in skeletal muscle. This muscle fiber transition decreased mitochondrial oxidative capacity and respiratory function. We hypothesized that the clenbuterol‐mediated reduction in oxidative capacity is associated with the alteration in mitochondrial morphology. To verify this hypothesis, we examined whether clenbuterol alters mitochondrial morphology and mitochondrial regulatory proteins in rat skeletal muscle. Clenbuterol was administered to rats via drinking water (30 mg/L) for 3 weeks. Myosin heavy chain (MHC) isoform composition, mitochondrial morphology, and fusion and fission regulatory protein levels in deep region and superficial region in tibialis anterior (TA) muscles were assessed. Clenbuterol induced the fiber type transition from slow to fast in both the regions of TA. The levels of optic atrophy protein 1, mitofusin 2, and mitochondrial fission 1, but not of dynamin‐related protein 1, significantly decreased in deep and superficial muscles after clenbuterol administration (P < 0.01). Also, observation using the transmission electron microscopy showed a decrease in mitochondrial volume (P < 0.05) and an increase in proportion of continuous or interacting mitochondria across Z‐lines (P < 0.05). We showed that clenbuterol administration induces a transition in the muscle fiber type composition toward fast phenotype and causes alterations in mitochondrial morphology with a concomitant decrease in mitochondrial fusion and fission regulatory protein levels. These mitochondrial morphological alterations may influence deleterious effects on skeletal muscle metabolism.

PERK regulates skeletal muscle mass and contractile function in adult mice.

Skeletal muscle mass is regulated by the coordinated activation of several anabolic and catabolic pathways. The endoplasmic reticulum (ER) is a major site of protein folding and a reservoir for calcium ions. Accretion of misfolded proteins or depletion in calcium concentration causes stress in the ER, which leads to the activation of a signaling network known as the unfolded protein response (UPR). In the present study, we investigated the role of the protein kinase R-like endoplasmic reticulum kinase (PERK) arm of the UPR in the regulation of skeletal muscle mass and function in naive conditions and in a mouse model of cancer cachexia. Our results demonstrate that the targeted inducible deletion of PERK reduces skeletal muscle mass, strength, and force production during isometric contractions. Deletion of PERK also causes a slow-to-fast fiber type transition in skeletal muscle. Furthermore, short hairpin RNA-mediated knockdown or pharmacologic inhibition of PERK leads to atrophy in cultured myotubes. While increasing the rate of protein synthesis, the targeted deletion of PERK leads to the increased expression of components of the ubiquitin-proteasome system and autophagy in skeletal muscle. Ablation of PERK also increases the activation of calpains and deregulates the gene expression of the members of the FGF19 subfamily. Furthermore, the targeted deletion of PERK increases muscle wasting in Lewis lung carcinoma tumor-bearing mice. Our findings suggest that the PERK arm of the UPR is essential for the maintenance of skeletal muscle mass and function in adult mice.-Gallot, Y. S., Bohnert, K. R., Straughn, A. R., Xiong, G., Hindi, S. M., Kumar, A. PERK regulates skeletal muscle mass and contractile function in adult mice.

Effects Of Sprint Interval Training On Apoptosis And MHC Gene Expression In Rat Skeletal Muscles

Physical exercise induces signaling pathways and regulatory molecules. It is believed that exercise can induce apoptosis which play important roles in retain of tissue and cellular homeostasis. FOXO1 has an important role to regulate apoptosis and induce fiber type transition in skeletal muscle. The effect of sprint interval training on apoptosis and fiber type transitions is unclear. PURPOSE: we examined response of FOXO1 as an important factor of apoptosis and fiber type transition in rat skeletal muscle after acute and chronic sprint interval exercise. METHODS: 24 male Sprague–Dawley rats (200–230 g) divided into 3 groups (n=8); chronic sprint interval (CSI), acute sprint interval (ASI), control (C). CSI was sprinting 1 min and 2–5 min rest between sets (6–10 sets/days, 5–6 days/weeks) on treadmill for 9 weeks. ASI was running with 10 m/min to 85 m/min which gradually increased in 3 consecutive days that included 7 sets of 1 min with rest interval of 3 min in between. Soleus and super vastus lateralis (SVL) muscles mRNA were analyzed by real-time RT-PCR. RESULTS: In soleus muscle, FoxO1 mRNA expression levels had a 1% decrease in ASI and 41% in CSI group compare to control group. In SVL muscle, FoxO1 mRNA expression had a 2% increase in ASI and a 37% decrease in CSI. No significant change in FOXO1 mRNA expression were observed between groups. Also, MHC I and IIa mRNA expression (0.3-, 0.4-fold) in soleus and MHC IIb (0.31-fold) in SVL decreased in CSI group, but in ASI, MHC I mRNA increased (3.69-fold) in SVL significantly (P≤0.05). CONCLUSION: FOXO1mRNA expression is more abundantly in fast muscle and probably has a limited effects on apoptosis in response to sprint interval training.

Regulation of metabolism: the work-to-rest transition in skeletal muscle.

The behavior of oxidative phosphorylation predicted by a model for the mechanism and kinetics of cytochrome c oxidase is compared with the experimentally observed behavior during the work-to-rest transition in skeletal muscle. For both experiment and model, when work stops, the increase in creatine phosphate and decrease in creatine and inorganic phosphate concentrations ([CrP], [Cr], and [Pi]) begin immediately. The rate of change for each is maximal and then progressively slows as the increasing energy state ([ATP]/[ADP][Pi]) suppresses the rate of oxidative phosphorylation. The time courses can be reasonably fitted to single exponential curves with similar time constants. The energy state in the working and resting steady states at constant Po2 are dependent on the intramitochondrial [NAD+]/[NADH], mitochondrial content, and size of the creatine pool ([CrP] + [Cr]). The rate of change in [CrP] is linearly correlated with [CrP] and with [Pi] and [Cr]. The time constant for [CrP] increase in the resting and working steady states, and the rate of decrease in oxygen consumption are similarly dependent on the Po2 in the inspired gas (experimental) or tissue Po2 (model). Myoglobin strongly buffers intracellular Po2 below ∼15 torr, truncating the low end of the oxygen distribution in the tissue and suppressing intra- and intermyocyte oxygen gradients. The predictions of the model are consistent with the experimental data throughout the work/rest transition, providing valuable insights into the regulation of cellular and tissue metabolism.

Regulation of metabolism: the rest-to-work transition in skeletal muscle.

Mitochondrial oxidative phosphorylation is programmed to set and maintain metabolic homeostasis, and understanding that program is essential for an integrated view of cellular and tissue metabolism. The behavior predicted by a mechanism-based model for oxidative phosphorylation is compared with that experimentally measured for skeletal muscle when work is initiated. For the model, initiation of work is simulated by imposing a rate of ATP utilization of either 0.6 (equivalent of 13.4 ml O2·100 g tissue(-1)·min(-1) or 6 μmol O2·g tissue(-1)·min(-1)) or 0.3 mM ATP/s. Creatine phosphate ([CrP]) decrease, both experimentally measured and predicted by the model, can be fit to a single exponential. Increase in ATP synthesis begins immediately but can show a "lag period," during which the rate accelerates. The length of the lag period is similar for both experiment and model; in the model, the lag depends on intramitochondrial [NAD(+)]/[NADH], mitochondrial content, and size of the creatine pool ([CrP] + [Cr]) as well as the resting [CrP]/[Cr]. For in vivo conditions, increase in oxygen consumption may be linearly correlated with a decrease in [CrP] and an increase in inorganic phosphate ([Pi]) and [Cr]. The decrease in [CrP], resting and working steady state [CrP], and the increase in oxygen consumption are dependent on the Po2 in the inspired gas (experimental) or tissue Po2 (model). The metabolic behavior predicted by the model is consistent with available experimental measurements in muscle upon initiation of work, with the model providing valuable insight into how metabolic homeostasis is set and maintained.

The promotion of a constructive macrophage phenotype by solubilized extracellular matrix

The regenerative healing response of injured skeletal muscle is dependent upon a heterogeneous population of responding macrophages, which show a phenotypic transition from the pro-inflammatory M1 to the alternatively activated and constructive M2 phenotype. Biologic scaffolds derived from mammalian extracellular matrix (ECM) have been used for the repair and reconstruction of a variety of tissues, including skeletal muscle, and have been associated with an M2 phenotype and a constructive and functional tissue response. The mechanism(s) behind in-vivo macrophage phenotype transition in skeletal muscle and the enhanced M2:M1 ratio associated with ECM bioscaffold use in-vivo are only partially understood. The present study shows that degradation products from ECM bioscaffolds promote alternatively activated and constructive M2 macrophage polarization in-vitro, which in turn facilitates migration and myogenesis of skeletal muscle progenitor cells.

TWEAK/Fn14 Signaling Axis Mediates Skeletal Muscle Atrophy and Metabolic Dysfunction

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) through binding to its receptor fibroblast growth factor inducible 14 (Fn14) has been shown to regulate many cellular responses including proliferation, differentiation, apoptosis, inflammation, and fibrosis, under both physiological and pathological conditions. Emerging evidence suggests that TWEAK is also a major muscle wasting cytokine. TWEAK activates nuclear factor-κB signaling and proteolytic pathways such as ubiquitin–proteasome system, autophagy, and caspases to induce muscle proteolysis in cultured myotubes. Fn14 is dormant or expressed in minimal amounts in normal healthy muscle. However, specific atrophic conditions, such as denervation, immobilization, and starvation stimulate the expression of Fn14 leading to activation of TWEAK/Fn14 signaling and eventually skeletal muscle atrophy. TWEAK also causes slow- to fast-type fiber transition in skeletal muscle. Furthermore, recent studies suggest that TWEAK diminishes mitochondrial content and represses skeletal muscle oxidative phosphorylation capacity. TWEAK mediates these effects through affecting the expression of a number of genes and microRNAs. In this review article, we have discussed the recent advancements toward understanding the role and mechanisms of action of TWEAK/Fn14 signaling in skeletal muscle with particular reference to different models of atrophy and oxidative metabolism.

Niacin supplementation induces type II to type I muscle fiber transition in skeletal muscle of sheep

BackgroundIt was recently shown that niacin supplementation counteracts the obesity-induced muscle fiber transition from oxidative type I to glycolytic type II and increases the number of type I fibers in skeletal muscle of obese Zucker rats. These effects were likely mediated by the induction of key regulators of fiber transition, PPARδ (encoded by PPARD), PGC-1α (encoded by PPARGC1A) and PGC-1β (encoded by PPARGC1B), leading to type II to type I fiber transition and upregulation of genes involved in oxidative metabolism. The aim of the present study was to investigate whether niacin administration also influences fiber distribution and the metabolic phenotype of different muscles [M. longissimus dorsi (LD), M. semimembranosus (SM), M. semitendinosus (ST)] in sheep as a model for ruminants. For this purpose, 16 male, 11 wk old Rhoen sheep were randomly allocated to two groups of 8 sheep each administered either no (control group) or 1 g niacin per day (niacin group) for 4 wk.ResultsAfter 4 wk, the percentage number of type I fibers in LD, SM and ST muscles was greater in the niacin group, whereas the percentage number of type II fibers was less in niacin group than in the control group (P < 0.05). The mRNA levels of PPARGC1A, PPARGC1B, and PPARD and the relative mRNA levels of genes involved in mitochondrial fatty acid uptake (CPT1B, SLC25A20), tricarboxylic acid cycle (SDHA), mitochondrial respiratory chain (COX5A, COX6A1), and angiogenesis (VEGFA) in LD, SM and ST muscles were greater (P < 0.05) or tended to be greater (P < 0.15) in the niacin group than in the control group.ConclusionsThe study shows that niacin supplementation induces muscle fiber transition from type II to type I, and thereby an oxidative metabolic phenotype of skeletal muscle in sheep as a model for ruminants. The enhanced capacity of skeletal muscle to utilize fatty acids in ruminants might be particularly useful during metabolic states in which fatty acids are excessively mobilized from adipose tissue, such as during the early lactating period in high producing cows.

Regulation of oxidative phosphorylation during work transitions results from its kinetic properties

The regulation of oxidative phosphorylation (OXPHOS) during work transitions in skeletal muscle and heart is still not well understood. Different computer models of this process have been developed that are characterized by various kinetic properties. In the present research-polemic theoretical study it is argued that models belonging to one group (Model A), which predict that among OXPHOS complexes complex III keeps almost all of the metabolic control over oxygen consumption (Vo2) and involve a strong complex III activation by inorganic phosphate (Pi), lead to the conclusion that an increase in Pi is the main mechanism responsible for OXPHOS activation (feedback-activation mechanism). Models belonging to another group (Model B), which were developed to take into account an approximately uniform distribution of metabolic control over Vo2 among particular OXPHOS complexes (complex I, complex III, complex IV, ATP synthase, ATP/ADP carrier, phosphate carrier) encountered in experimental studies in isolated mitochondria, predict that all OXPHOS complexes are directly activated in parallel with ATP usage and NADH supply by some external cytosolic factor/mechanism during rest-to-work or low-to-high work transitions in skeletal muscle and heart ("each-step-activation" mechanism). Model B demonstrates that different intensities of each-step activation can account for the very different (slopes of) phenomenological Vo2-ADP relationships observed in various skeletal muscles and heart. Thus they are able to explain the differences in the regulation of OXPHOS during work transitions between skeletal muscle (where moderate changes in ADP take place) and intact heart in vivo (where ADP is essentially constant).

Regulation of anaerobic glycolysis during work transitions in skeletal muscle: In silico studies

Regulation of anaerobic glycolysis during work transitions in skeletal muscle: In silico studies

Cycling exercise-induced myofiber transitions in skeletal muscle depend on basal fiber type distribution

The link between specific changes in myofiber type proportions and modulation of training in human skeletal muscle has yet to be unraveled. We investigated whether a defined increase in training volume induces a corresponding change of myofiber shifting in human skeletal muscle with distinct basal myofiber distribution. Twenty-one male cyclists (Age 26 ± 4 years) with different performance levels were exposed to increased cycling training volume with reduced power output for 3 months. Biopsies were taken from vastus lateralis muscle PRE-POST and the proportions of type I, IIa, IIx and IIc myofibers were determined. Total training time did not correlate to the degree of fiber type shifting of any type. In the entire sample of subjects, the proportion of type I myofibers tended to increase (P = 0.14) while IIa fibers decreased significantly (P < 0.05). Subgroups of subjects possessing higher (HPS) and lower proportions (LPS) of type I myofibers at baseline showed a distinct pattern in changing myofiber distribution. Subjects in HPS offered no change in myofiber proportions of any type. In contrast, subjects in LPS showed marked increases in type I (P = 0.06) and a significant reduction in IIa myofibers (P = 0.01). An inverse correlation between baseline proportion of type I and IIa myofibers and its change was observed. We conclude that individual myofiber composition constitutes a modulating factor for exercise-induced changes in its distribution. This might be influenced by altered demands of myofiber recruitment in relation to the intensity of muscle contraction but also by its relative abundance in contracting muscle.

Exercise in hypertension: do skeletal muscle reflexes make this a dangerous proposition?

the benefits of exercise and exercise training are numerous, varying from increasing skeletal muscle strength to enhancing cardiovascular and respiratory fitness. These attributes of exercise are key elements to the maintenance of good health and the improvement of athletic performance. But are

Antidiabetic sulphonylureas activate mitochondrial permeability transition in rat skeletal muscle

Antidiabetic sulphonylureas can bind to various intracellular organelles including mitochondria. The aim of this study was to monitor the influence of antidiabetic sulphonylureas on membrane permeability in mitochondria isolated from rat skeletal muscle. The effects of glibenclamide (and other sulphonylurea derivatives) on mitochondrial function were studied by measuring mitochondrial swelling, mitochondrial membrane potential, respiration rate and Ca2+ transport into mitochondria. We observed that glibenclamide induced mitochondrial swelling (EC50 = 8.2 +/- 2.5 microM), decreased the mitochondrial membrane potential and evoked Ca2+ efflux from the mitochondrial matrix. These effects were blocked by 2 microM cyclosporin A, an inhibitor of the mitochondrial permeability transition. Moreover, 30 microM glibenclamide accelerated the respiratory rate in the presence of glutamate/malate, substrates of complex I of the mitochondrial respiratory chain. In conclusion, we postulate that the antidiabetic sulphonylureas activate the mitochondrial permeability transition in skeletal muscle by increasing its sensitivity to Ca2+.

Intracellular [H+]: a determinant of cell volume in skeletal muscle

Intracellular [H⁺]: a determinant of cell volume in skeletal muscle

Dynamics of microvascular oxygen pressure during rest-contraction transition in skeletal muscle of diabetic rats.

Type I diabetes reduces dramatically the capacity of skeletal muscle to receive oxygen (QO(2)). In control (C; n = 6) and streptozotocin-induced diabetic (D: n = 6, plasma glucose = 25.3 +/- 3.9 mmol/l and C: 8.3 +/- 0.5 mmol/l) rats, phosphorescence quenching was used to test the hypothesis that, in D rats, the decline in microvascular PO(2) [Pm(O(2)), which reflects the dynamic balance between O(2) utilization (VO(2)) and QO(2)] of the spinotrapezius muscle after the onset of electrical stimulation (1 Hz) would be faster compared with that of C rats. Pm(O(2)) data were fit with a one or two exponential process (contingent on the presence of an undershoot) with independent time delays using least-squares regression analysis. In D rats, Pm(O(2)) at rest was lower (C: 31.2 +/- 3.2 mmHg; D: 24.3 +/- 1.3 mmHg, P < 0.05) and at the onset of contractions decreased after a shorter delay (C: 13.5 +/- 1.8 s; D: 7.6 +/- 2.1 s, P < 0.05) and with a reduced mean response time (C: 31.4 +/- 3.3 s; D: 23.9 +/- 3.1 s, P < 0.05). Pm(O(2)) exhibited a marked undershoot of the end-stimulation response in D muscles (D: 3.3 +/- 1.1 mmHg, P < 0.05), which was absent in C muscles. These results indicate an altered VO(2)-to-QO(2) matching across the rest-exercise transition in muscles of D rats.

Evidence of a slow-to-fast fiber type transition in skeletal muscle from spontaneously hypertensive rats

The histochemical, biochemical, and electrophysiological properties of selected muscles were evaluated in spontaneously hypertensive rats (SHR) and compared with their normotensive Wistar-Kyoto (WKY) counterparts. As early as 4 wk of age, slow muscles (soleus) of SHR displayed a significant alteration in fiber type distribution with a decrease of slow-twitch fibers (from 64 to 53%) and a simultaneous increase of type IIA-fibers (from 19 to 39%). In addition, soleus from young SHR had a significant enhancement of both oxidative (citrate synthase, 3-hydroxyacyl-CoA dehydrogenase) and glycolytic [lactate dehydrogenase (LDH)] capacities, which could be partly related to a capillary rarefaction. During development (from the 4th to the 12-14th wk), in the soleus muscle the histochemical differences between SHR and WKY were amplified, whereas most of the enzymatic differences between strains were abolished, except for a significantly higher LDH activity. These histochemical changes had only marginal repercussions on soleus electrophysiological properties. SHR animals had a significantly higher basal metabolic rate, which could not be accounted for by elevation of thyroid hormones. The origin of the slow-to-fast fiber type transition in slow muscle remains unclear but could be related to the increased level of plasma catecholamines in SHR. Indeed, chronic treatment of rats with a beta 2-receptor agonist has been reported to cause slow-to-fast muscle fiber transition [R. J. Zeman, R. Ludemann, T. G. Easton, and J. D. Etlinger. Am. J. Physiol. 254 (Endocrinol. Metab. 17): E726-E732, 1988].

Why is there a delay in the increased oxygen consumption during the rest-work transition in skeletal muscle?

During the rest-work transition in skeletal muscle it has long been known that the increase in oxidative supply of ATP lags the increase in consumption of ATP. The balance is supplied by muscle stores of phosphocreatine (PCr) and glycolysis leading to accumulation of lactate in the muscle. Several hypotheses have been advanced to account for the lag in increase of \(\dot{V}{{O}_{2}}\). These have focused on limits to the delivery of substrates to the mitochondrion: 1) limiting oxygen supply 2) limiting supply of reducing equivalents 3) limiting ADP and/or phosphate (Pi) KeywordsGracilis MuscleAdenine Nucleotide TranslocaseHigh Energy PhosphateEnergy TurnoverCreatine Kinase ReactionThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Histochemical, biochemical, and contractile properties of red, white, and intermediate fibers.

Histochemical, biochemical, and contractile properties of red, white, and intermediate fibers.