Slow Muscle Fibers Research Articles

Luteolin increases slow muscle fibers via FLCN-AMPK-PGC-1α signaling pathway

• Luteolin may improve endurance exercise capacity of mice. • Luteolin may increase slow muscle fibers proportion both in mice and C2C12 myotubes. • Luteolin may activate FLCN-AMPK-PGC-1α axis in mice’s muscle and C2C12 myotubes. • FLCN-AMPK-PGC-1α axis may play key role in luteolin induced slow myofibers increasing. While the regulating mechanisms of slow myofibers have been gradually explored, there are currently a lack of effective means to increase slow myofibers proportion. Here, we have showed that luteolin could markedly improve endurance exercise performance and increase body oxygen consumption of mice, and activate aerobic enzyme activity and slow myofibers related genes and proteins expression in mice’s skeletal muscle. Meanwhile, folliculin (FLCN)-AMP-activated protein kinase (AMPK) -peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) pathway was activated by treatment luteolin in the tissues. Furthermore, by in vitro investigation and FLCN lentivirus infection, we have found that the over-expression of FLCN significantly reduces the effects of luteolin on slow myofibers expression and AMPK-PGC-1α axis activation. Together, our results indicate that luteolin can increase the proportion of slow myofibers probably by FLCN-AMPK-PGC-1α pathway. These findings provide a novel approach to increase slow muscle fibers proportion and improve skeletal muscle fitness.

A case report of deglutition triggered atrial fibrillation in a patient with Laing distal myopathy

BackgroundDeglutition-induced atrial fibrillation is a rare clinical entity with a reported prevalence of 0.6%. Laing distal myopathy is a rare autosomal dominant muscular dystrophy that is the result of mutations within the slow skeletal muscle fibre myosin heavy chain gene (MYH7). Atrial fibrillation has not been previously reported in patients with Laing distal myopathy. We describe the first reported case of deglutition triggered atrial fibrillation in a female with a history of Laing distal myopathy.Case summaryA 44-year-old female with a history of Laing distal myopathy diagnosed at age 32, began experiencing intermittent episodes of pre-syncope and palpitations which occurred after deglutition with food. An ambulatory 30-day patient triggered event monitor recorded episodes of atrial fibrillation with rapid ventricular response. Family history was significant for Laing distal myopathy, atrial fibrillation, as well as sudden cardiac death. Laboratory data, transthoracic echocardiogram, cardiac magnetic resonance imaging, and an exercise treadmill SPECT Imaging stress test were normal. An oesophagram revealed a mild oesophageal dysmotility with no other abnormalities. She was started on flecainide 50 mg p.o. every 8 h and verapamil 40 mg p.o. every 8 h with no further episodes of atrial fibrillation.DiscussionGiven the strong genetic component of this myopathy, one could postulate as to a possible genetic component in the development of atrial fibrillation in our patient. Although we cannot make definite correlation between deglutition-induced atrial fibrillation and Laing myopathy, it is important to report this unusual association which has not been described before.

Changes in use of slow and fast twitch muscle fibers in diabetics with and without neuropathy during gait

In part I of this study, we investigated the elastic Cherenkov effect (ECE) in an incompressible transversely isotropic (TI) soft solid using a combined theoretical and computational approach, based on which an inverse method has been proposed to measure both the anisotropic and hyperelastic parameters of TI soft tissues. In this part, experiments were carried out to validate the inverse method and demonstrate its usefulness in practical measurements. We first performed ex vivo experiments on bovine skeletal muscles. Not only the shear moduli along and perpendicular to the direction of muscle fibers but also the elastic modulus EL and hyperelastic parameter c2 were determined. We next carried out tensile tests to determine EL, which was compared with the value obtained using the shear wave elastography method. Furthermore, we conducted in vivo experiments on the biceps brachii and gastrocnemius muscles of ten healthy volunteers. To the best of our knowledge, this study represents the first attempt to determine EL of human muscles using the dynamic elastography method and inverse analysis. The significance of our method and its potential for clinical use are discussed.

Passive static stretching alters the characteristics of the force-velocity curvature differently for fast and slow muscle groups-A practical application of Hill's equation.

Studies showed fast muscle fibers have a greater constant b value of Hill's equation than that of slow muscle fibers, and the changing ratio of b/Vmax indicates the altered characteristics of muscles under certain conditions such as static stretching. This study was to investigate the effect of acute passive static stretching on the curvature of force-velocity curve in people with different muscle fiber types. A two-step work was conducted in current study through using Hill's equation: 1) calculated b values for each subject at different conditions (non-stretched and stretched) to determine muscle groups, and 2) examined the effect of static stretching on different muscle groups. Sixty-five college students performed isokinetic leg extensions at 5 speeds to test peak torque, following either a non-stretching or two passive static quadriceps stretching exercises. The peak torque and corresponding velocity were used to calculate the b constant. Data reduction consisted of calculating a Z score for each non-stretched and stretched b values. Individuals, whose non-stretched b constant was above or below one standard deviation of the Z score, were designated as the less curved (fast) and more curved (slow) groups, respectively. A paired t-test was used to analyze the pre and post intervention effect on b values for each group (p<0.05). This study found passive static stretching significantly altered the b constant of the fast group, but no effect on slow group. Therefore, we suggest static stretching should be avoided immediately before fast or explosive activities in individuals using predominantly fast muscle fibers.

Naringin Promotes Skeletal Muscle Fiber Remodeling by the AdipoR1-APPL1-AMPK Signaling Pathway.

Naringin, a natural flavonoid mainly found in citrus fruit, has been reported to exert a positive effect on improving skeletal muscle health. However, the effects and potential mechanisms of naringin on skeletal muscle fiber switching is still unclear. Here, we discovered that oral administration of naringin increased the low-speed running time, four-limb hanging time, body oxygen consumption in mice, enhanced aerobic enzyme activity, MyHC I expression, and slow-twitch fiber percentage in mice skeletal muscle. By contrast, naringin decreased α-GPDH enzyme activity, MyHC IIb expression, and fast-twitch fiber percentage. Moreover, naringin increased the concentration of serum adiponectin and activated the expression of AdipoR1, APPL1, AMPK, and PGC-1α. Furthermore, by the in vitro experiment and AdipoR1 knockdown, we found that inhibition of the AdipoR1 signaling pathway significantly reduced the effect of naringin on slow-twitch fiber-/fast-twitch fiber-related gene and protein expression. In conclusion, our results indicated that naringin could induce skeletal muscle fiber transition from fast twitch to slow twitch via the AdipoR1 signaling pathway. This study may provide new strategy for improving exercise endurance and slow muscle fiber deficiency-related diseases.

LGMD: EP.188 Elevation of fast but not slow muscle fiber injury biomarkers after exercise in Becker and LGMDR9 muscular dystrophies

Patients with muscular dystrophies (MDs) experience progressive muscle damage. A key approach to understand the nature and dynamics of the muscle damage is to examine the biomarker response to exercise. Type I and II muscle fibers differ in their troponin I (TnI) isoforms. We examined circulating TnI isoform response to exercise in patients with Becker (BMD) and, limb-girdle (LGMD) types R9 (FKRP) and R12 (ANO5) muscular dystrophies, as well as healthy controls. 27 subjects (6 BMD, 3 FKRP, 9 ANO5 and 9 controls) have been studied thus far.

What's all the hype with fibre type? Selective single fibre adaptations with lifelong endurance exercise.

What's all the hype with fibre type? Selective single fibre adaptations with lifelong endurance exercise.

Regulation of the Expression of the Myosin Heavy Chain (MYH) Gene myh14 in Zebrafish Development.

The human sarcomeric myosin heavy chain gene MYH14 contains an intronic microRNA, miR-499. Our previous studies demonstrated divergent genomic organization and expression patterns of myh14/miR-499 among teleosts; however, the regulatory mechanism is partly known. In this study, we report the regulation of myh14 expression in zebrafish, Danio rerio. Zebrafish myh14 has three paralogs, myh14-1, myh14-2, and myh14-3. Detailed promoter analysis suggested that a 5710-bp 5'-flanking region of myh14-1 and a 5641-bp region of myh14-3 contain a necessary regulatory region to recapitulate specific expression during embryonic development. The 5'-flanking region of zebrafish myh14-1 and its torafugu ortholog shared two distal and a single proximal conserved region. The two distal conserved regions had no effect on zebrafish myh14-1 expression, in contrast to torafugu expression, suggesting an alternative regulatory mechanism among the myh14 orthologs. Comparison among the 5'-flanking regions of the myh14 paralogs revealed two conserved regions. Deletion of these conserved regions significantly reduced the promoter activity of myh14-3 but had no effect on myh14-1, indicating different cis-regulatory mechanisms of myh14 paralogs. Loss of function of miR-499 resulted in a marked reduction in slow muscle fibers in embryonic development. Our study identified different cis-regulatory mechanisms controlling the expression of myh14/miR-499 and an indispensable role of miR-499 in muscle fiber-type specification in zebrafish.

Prolonged caloric restriction ameliorates age-related atrophy in slow and fast muscle fibers of rat soleus muscle

Aging causes loss of skeletal muscle mass and function, which is called sarcopenia. While sarcopenia impairs the quality of life of older adults and is a major factor in long-term hospitalization, its detailed pathogenic mechanism and preventive measures remain to be identified. Caloric restriction (CR) suppresses age-related physiological and pathological changes in many species and prolongs the average and healthy life expectancy. It has recently been reported that CR suppresses the onset of sarcopenia; however, few studies have analyzed the effects of long-term CR on age-related skeletal muscle atrophy. Thus, we investigated the aging and CR effects on soleus (SOL) muscles of 9-, 24-, and 29-month-old ad libitum-fed rats (9AL, 24AL, and 29AL, respectively) and of 29-month-old CR (29CR) rats. The total muscle cross sectional area (mCSA) of the entire SOL muscle significantly decreased in the 29AL rats, but not in the 24AL rats, compared with the 9AL rats. SOL muscle of the 29AL rats exhibited marked muscle fiber atrophy and increases in the number of muscle fibers with a central nucleus, in fibrosis, and in adipocyte infiltration. Additionally, although the decrease in the single muscle fiber cross-sectional area (fCSA) and the muscle fibers' number occurred in both slow-type and fast-type muscle fibers, the degree of atrophy was more remarkable in the fast-type fibers. However, CR suppressed the muscle fiber atrophy observed in the 29AL rats' SOL muscle by preserving the mCSA and the number of muscle fibers that declined with aging, and by decreasing the number of muscle fibers with a central nucleus, fibrosis and denervated muscle fibers. Overall, these results revealed that advanced aging separately reduces the number and fCSA of each muscle fiber type, but long-term CR can ameliorate this age-related sarcopenic muscle atrophy.

Comparative Effects Of Two Exercise Modalities On Mots-c Levels In Rats

The mitochondrial-derived peptide MOTS-c is an important cyto-protector in helping maintain mitochondrial function and cellular viability, and regulating metabolic homeostasis. It is important to understand the effects of different exercise modalities on MOTS-c levels in various physiological systems in order to identify its role as a signal of physical exercise. PURPOSE: To explore the comparative effects of moderate-intensity aerobic exercise and resistance exercise on levels of MOTS-c in the serum, skeletal muscle and heart. METHODS: Thirty male Sprague-Dawley (SD) rats were randomly divided into three groups: a control group (C, n = 10), an aerobic exercise group (A, n = 10) and a resistance exercise group (R, n = 10). Rats in the A group ran on a treadmill at 21 m/min for 60 min per day, 5 days per week, while rats in the R group climbed a ladder with incremental loads (50%, 75%, 90% and 100% 1RM respectively, 3 times/level, 5 days per week). The training period lasted for 4 weeks. Resting MOTS-c levels in the serum, skeletal muscle, and myocardium were evaluated by enzyme-linked immunosorbent assays, and group differences in MOTS-c levels were determined by using one-way ANOVAs with post-hoc tests. RESULTS: Serum MOTS-c levels were significantly higher in A and R rats compared to C rats (both p < 0.01). No difference in serum MOTS-c levels was found between A and R rats. A significant effect of interaction between fiber type and exercise modality was found on skeletal muscle MOTS-c levels. MOTS-c levels in soleus were significantly higher in A rats compared to C and R rats (p < 0.01 and p < 0.05, respectively), while MOTS-c levels in gastrocnemius were significantly higher in R rats compared to C and A rats (both p < 0.05). Myocardial MOTS-c levels were significantly higher in A rats compared to C rats (p < 0.01), while no difference was found between R and C rats. CONCLUSION: Both exercise modalities increased MOTS-c levels in the serum, and induced MOTS-c uptake into the skeletal muscle. Aerobic exercise may be more effective in facilitating MOTS-c uptake into slow twitch muscle fibers and myocardium. Further research is warranted to clarify the underlying mechanisms. (This study was funded by National Natural Science Foundation of China: Grant Number 31971104)

Theaflavin Promotes Mitochondrial Abundance and Glucose Absorption in Myotubes by Activating the CaMKK2-AMPK Signal Axis via Calcium-Ion Influx.

Drinking tea has been proven to have a positive biological effect in regulating human glucose and lipid metabolism and preventing type 2 diabetes (T2D). Skeletal muscle (SkM) is responsible for 70% of the sugar metabolism in the human body, and its dysfunction is an important factor leading to the development of obesity, T2D, and muscle diseases. As one of the four known theaflavins (TFs) in black tea, the biological role of theaflavin (TF1) in regulating SkM metabolism has not been reported. In this study, mature myotubes induced by C2C12 cells in vitro were used as models. The results showed that TF1 (20 μM) promoted mitochondrial abundance and glucose absorption in myotubes by activating the CaMKK2-AMPK signaling axis via Ca2+ influx. Moreover, it promoted the expression of slow muscle fiber marker genes (Myh7, Myl2, Tnnt1, and Tnnc1) and PGC-1α/SIRT1, as well as enhanced the oxidative phosphorylation capacity of myotubes. In conclusion, this study preliminarily clarified the potential role of TF1 in regulating SkM glucose absorption as well as promoting SkM mitochondrial biosynthesis and slow muscle fiber formation. It has potential research and application values for the prevention/alleviation of SkM-related T2D and Ca2+-related skeletal muscle diseases through diet.

Hind foot drumming: Myosin heavy chain muscle fiber distribution in the hind limb muscles of three African mole-rat species (Bathyergidae).

Hind foot drumming as a form of seismic signaling plays a pivotal role in the communication of various mammalian species including Bathyergidae (African mole-rats). The aim of the present study was to histologically determine if the action of hind foot drumming would influence the number of type II fibers present in the hind limb muscles of two drumming (Georychus capensis and Bathyergus suillus) and one non-drumming (Cryptomys hottentotus natalensis) bathyergid species. Twenty-one frozen muscles of each species were selected for the purpose of mid-belly cryostat sections. These sections were immunohistochemically labeled for myosin heavy chain slow muscle fibers (MHCs). In addition, oxidative capacity was determined by means of histochemical staining. A high percentage of fast type II muscle fibers was found in all the functional muscle groups, although there were no statistical differences between the drumming and non-drumming species. Bathyergus suillus had significantly fewer type II fibers in mm. semitendinosus, gluteofemoralis, tibialis cranialis, plantaris, and the medial head of m. gastrocnemius compared to the other two species. In all three species, the majority of the muscle fibers in all functional muscle groups demonstrated low oxidative capacity which correlated with the expression of type II muscle fibers. It therefore seems likely that the number of type II muscle fibers in the hind limb muscles of the Bathyergidae species studied here is more influenced by either body size or digging strategy rather than being an adaptation for hind foot drumming.

Effect of maternal overnutrition on predisposition to insulin resistance in the foal: Foal skeletal muscle development and insulin signaling

Skeletal muscle plays an integral role in the ability of a horse to perform at high levels. Shifts in skeletal muscle development in response to maternal plane of nutrition may have substantial and lasting impacts on athletic performance and whole-body metabolism. Therefore, sixteen Quarter Horse mares were used in a completely randomized design and maintained at a body condition score (BCS) 6 until start of third trimester. On d 235 of gestation, mares were randomly assigned to receive one of two dietary treatments with a diet formulated to meet requirements during late gestation (CON; n = 8), and an overfed diet (HIGH; n = 8) where mares received an additional 40% above CON. Five h after parturition, foals were euthanized, and gluteus medius, triceps brachii, and semitendinosus were harvested for analyses. Gene expression was determined by qPCR and western immunoblotting was used to quantify total and phosphorylated forms of proteins involved in skeletal muscle metabolism with tubulin as the loading control. All data were analyzed using PROC MIXED of SAS. Foals from HIGH mares exhibited larger skeletal muscle fibers by area (P <0.05), and a shift in muscle fiber development towards type I slow twitch muscle fibers (P <0.05). Relative expression of glucose transporter 4 (GLUT4) was lower in HIGH foals compared to CON in gluteus medius (P = 0.05). Insulin receptor isoform B (INSR-B) and insulin-like growth factor 1 receptor (IGF1R) were greater in triceps brachii of HIGH foals compared to CON (P ≤ 0.03). Insulin receptor isoform A (INSR-A), however, tended to be lower in triceps brachii of HIGH compared to CON (P = 0.10). Ratios of phosphorylated to total extracellular signal-regulated protein kinase 1/2 (ERK1/2) and c-June N-terminal kinase (JNK) were higher in HIGH foals compared to CON (P ≤0.04) in gluteus medius. There were no differences observed for phosphorylated to total protein ratios in semitendinosus and triceps brachii muscles; however, total ERK1/2 tended to be elevated (P <0.10) in semitendinosus from CON foals compared to HIGH. There was no difference in phosphorylated or total protein kinase B (AKT) (P >0.14). These data indicate hypertrophy of skeletal muscle fibers and a shift towards type I slow twitch fibers in HIGH foals. Furthermore, this study identifies muscle specific changes in gene expression and downstream insulin receptor signaling, which may contribute to future metabolic abnormalities in response to maternal overnutrition.

Comparison of Shear Wave Elastography and Dynamometer Test in Muscle Tissue Characterization for Potential Medical and Sport Application.

Skeletal muscle status and its dynamic follow up are of particular importance in the management of several diseases where weight and muscle mass loss and, consequently, immobilization occurs, as in cancer and its treatment, as well as in neurodegenerative disorders. But immobilization is not the direct result of body and muscle mass loss, but rather the loss of the maximal tension capabilities of the skeletal muscle. Therefore, the development of a non-invasive and real-time method which can measure muscle tension capabilities in immobile patients is highly anticipated. Our aim was to introduce and evaluate a special ultrasound measurement technique to estimate a maximal muscle tension characteristic which can be used in medicine and also in sports diagnostics. Therefore, we determined the relationship between the results of shear wave elastography measurements and the dynamometric data of individuals. The measurements were concluded on the m. vastus lateralis. Twelve healthy elite athletes took part in our preliminary proof of principle study—five endurance (S) and seven strength (F) athletes showing unambiguously different muscle composition features, nine healthy subjects (H) without prior sports background, and four cancer patients in treatment for a stage 3 brain tumor (T). Results showed a high correlation between the maximal dynamometric isometric torque (Mmax) and mean elasticity value (E) for the non-athletes [(H + T), (r = 0.795)] and for the athletes [(S + F), (r = 0.79)]. For the athletes (S + F), the rate of tension development at contraction (RTDk) and E correlation was also determined (r = 0.84, p < 0.05). Our measurements showed significantly greater E values for the strength athletes with fast muscle fiber dominance than endurance athletes with slow muscle fiber dominance (p < 0.05). Our findings suggest that shear wave ultrasound elastography is a promising method for estimating maximal muscle tension and, also, the human skeletal muscle fiber ratio. These results warrant further investigations with a larger number of individuals, both in medicine and in sports science.

Single muscle fibre contractile characteristics with lifelong endurance exercise.

A hallmark trait of ageing skeletal muscle health is a reduction in size and function, which is most pronounced in the fast muscle fibres. We studied older men (74±4years) with a history of lifelong (>50years) endurance exercise to examine potential benefits for slow and fast muscle fibre size and contractile function. Lifelong endurance exercisers had slow muscle fibres that were larger, stronger, faster and more powerful than young exercisers (25±1years) and age-matched non-exercisers (75±2years). Limited benefits with lifelong endurance exercise were noted in the fast muscle fibres. These findings suggest that additional exercise modalities (e.g. resistance exercise) or other therapeutic interventions are needed to target fast muscle fibres with age. We investigated single muscle fibre size and contractile function among three groups of men: lifelong exercisers (LLE) (n=21, 74±4years), old healthy non-exercisers (OH) (n=10, 75±2years) and young exercisers (YE) (n=10, 25±1years). On average, LLE had exercised ∼5 daysweek-1 for ∼7 hweek-1 over the past 53±6years. LLE were subdivided based on lifelong exercise intensity into performance (LLE-P) (n=14) and fitness (LLE-F) (n=7). Muscle biopsies (vastus lateralis) were examined for myosin heavy chain (MHC) slow (MHC I) and fast (MHC IIa) fibre size and function (strength, speed, power). LLE MHC I size (7624±2765μm2 ) was 25-40% larger (P<0.001) than YE (6106±1710μm2 ) and OH (5476±2467μm2 ). LLE MHC I fibres were ∼20% stronger, ∼10% faster and ∼30% more powerful than YE and OH (P<0.05). By contrast, LLE MHC IIa size (6466±2659μm2 ) was similar to OH (6237±2525μm2 ; P=0.854), with both groups ∼20% smaller (P<0.001) than YE (7860±1930μm2 ). MHC IIa contractile function was variable across groups, with a hierarchical pattern (OH > LLE > YE; P<0.05) in normalized power among OH (16.7±6.4WL-1 ), LLE (13.9±4.5WL-1 ) and YE (12.4±3.5WL-1 ). The LLE-P and LLE-F had similar single fibre profiles with MHC I power driven by speed (LLE-P) or force (LLE-F), suggesting exercise intensity impacted slow muscle fibre mechanics. These data suggest that lifelong endurance exercise benefited slow muscle fibre size and function. Comparable fast fibre characteristics between LLE and OH, regardless of training intensity, suggest other exercise modes (e.g. resistance training) or myotherapeutics may be necessary to preserve fast muscle fibre size and performance with age.

The stress responsive gene ankrd1a is dynamically regulated during skeletal muscle development and upregulated following cardiac injury in border zone cardiomyocytes in adult zebrafish.

Ankyrin repeat domain 1 (ANKRD1) is a functionally pleiotropic protein found in the nuclei and sarcomeres of cardiac and skeletal muscles, with a proposed role in linking myofibrilar stress and transcriptional regulation. Rapid upregulation of its expression in response to both physiological and pathological stress supports the involvement of ANKRD1 in muscle tissue adaptation and remodeling. However, the exact role of ANKRD1 remains poorly understood. To begin to investigate its function at higher resolution, we have generated and characterized a TgBAC(ankrd1a:EGFP) zebrafish line. This reporter line displays transgene expression in slow skeletal muscle fibers during development and exercise responsiveness in adult cardiac muscle. To better understand the role of Ankrd1a in pathological conditions in adult zebrafish, we assessed ankrd1a expression after cardiac ventricle cryoinjury and observed localized upregulation in cardiomyocytes in the border zone. We show that this expression in injured hearts is recapitulated by the TgBAC(ankrd1a:EGFP) reporter. Our results identify novel expression domains of ankrd1a and suggest an important role for Ankrd1a in the early stress response and regeneration of cardiac tissue. This new reporter line will help decipher the role of Ankrd1a in striated muscle stress response, including after cardiac injury.

Multifidus Muscle Fiber Type Distribution is Changed in Mouse Models of Chronic Intervertebral Disc Degeneration, but is not Attenuated by Whole Body Physical Activity.

Case-controlled animal study. The aim of this study was to investigate whether multifidus muscle fiber type distribution changes in models of interverbal disc (IVD) degeneration and whether this is resolved by physical activity (PA). The loss of slow type I muscle fibers in the multifidus muscle in people with low back pain is contentious. Data from animal models of IVD degeneration suggest some discrepancies in human studies might be explained by the dependence of slow muscle fiber changes and their underlying mechanisms, on the time since injury and progression of IVD degeneration. It is not yet resolved what changes are apparent once the chronic phase is established. It is also not known whether muscle fiber changes can be resolved by whole body PA. This study aimed to examine slow fiber distribution in the multifidus muscle in models of IVD injury or spontaneous degeneration in animals with or without exposure to PA. Two models of IVD degeneration were used. The first model used a genetically modified mouse (SPARC-null) that spontaneously develops IVD degeneration. The second model involved a surgically induced IVD lesion to induce degeneration. Mice in each study were allocated to housing with or without a running wheel for PA. At 12 months of age, the multifidus muscle was harvested. Slow muscle fiber distribution and the mRNA expression of genes associated with muscle fiber type transformation were examined. The proportion and cross-sectional area of slow muscle fibers were reduced in both models of IVD degeneration compared to controls, without evidence of ongoing fiber transformation. Whole-body PA did not attenuate these alterations. Results confirmed slow muscle fiber loss in the multifidus in the chronic phase of IVD degeneration induced spontaneously and by injury. Whole-body PA did not attenuate changes to muscle fiber distribution. More specific approaches to muscle activation might be required to achieve more complete reversal of muscle fiber changes, with potential implications for therapy in humans.Level of Evidence: N/A.

Angiotensin 1-7 protects against ventilator-induced diaphragm dysfunction.

Mechanical ventilation (MV) is a life‐saving instrument used to provide ventilatory support for critically ill patients and patients undergoing surgery. Unfortunately, an unintended consequence of prolonged MV is the development of inspiratory weakness due to both diaphragmatic atrophy and contractile dysfunction; this syndrome is labeled ventilator‐induced diaphragm dysfunction (VIDD). VIDD is clinically important because diaphragmatic weakness is an important contributor to problems in weaning patients from MV. Investigations into the pathogenesis of VIDD reveal that oxidative stress is essential for the rapid development of VIDD as redox disturbances in diaphragm fibers promote accelerated proteolysis. Currently, no standard treatment exists to prevent VIDD and, therefore, developing a strategy to avert VIDD is vital. Guided by evidence indicating that activation of the classical axis of the renin‐angiotensin system (RAS) in diaphragm fibers promotes oxidative stress and VIDD, we hypothesized that activation of the nonclassical RAS signaling pathway via angiotensin 1‐7 (Ang1‐7) will protect against VIDD. Using an established animal model of prolonged MV, our results disclose that infusion of Ang1‐7 protects the diaphragm against MV‐induced contractile dysfunction and fiber atrophy in both fast and slow muscle fibers. Further, Ang1‐7 shielded diaphragm fibers against MV‐induced mitochondrial damage, oxidative stress, and protease activation. Collectively, these results reveal that treatment with Ang1‐7 protects against VIDD, in part, due to diminishing oxidative stress and protease activation. These important findings provide robust evidence that Ang1‐7 has the therapeutic potential to protect against VIDD by preventing MV‐induced contractile dysfunction and atrophy of both slow and fast muscle fibers.

Skeletal muscle-specific Keap1 disruption modulates fatty acid utilization and enhances exercise capacity in female mice

Skeletal muscle health is important for the prevention of various age-related diseases. The loss of skeletal muscle mass, which is known as sarcopenia, underlies physical disability, poor quality of life and chronic diseases in elderly people. The transcription factor NRF2 plays important roles in the regulation of the cellular defense against oxidative stress, as well as the metabolism and mitochondrial activity. To determine the contribution of skeletal muscle NRF2 to exercise capacity, we conducted skeletal muscle-specific inhibition of KEAP1, which is a negative regulator of NRF2, and examined the cell-autonomous and non-cell-autonomous effects of NRF2 pathway activation in skeletal muscles. We found that NRF2 activation in skeletal muscles increased slow oxidative muscle fiber type and improved exercise endurance capacity in female mice. We also observed that female mice with NRF2 pathway activation in their skeletal muscles exhibited enhanced exercise-induced mobilization and β-oxidation of fatty acids. These results indicate that NRF2 activation in skeletal muscles promotes communication with adipose tissues via humoral and/or neuronal signaling and facilitates the utilization of fatty acids as an energy source, resulting in increased mitochondrial activity and efficient energy production during exercise, which leads to improved exercise endurance.

ECTOPIC TWEAKR EXPRESSION IN TYPE I FIBER OF STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS IS RELATED TO SLOW MUSCLE-SPECIFIC HYPOTROPHY THROUGH MURF1 OVEREXPRESSION

Objective: The maintenance of muscle strength and mass is important for body homeostasis. Stroke-prone spontaneously hypertensive rats (SHRSP) show significantly higher blood pressure and lower body weight than normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). In addition, blood pressure and body weight show an inverse correlation among the rats. We hypothesized that skeletal muscle hypotrophy in hypertensive rats is related to hypertension-related diseases and is useful as a therapeutic target for hypertension and hypertension-related diseases. We aimed to investigate the pathophysiological characteristics of muscle hypotrophy in SHRSP to determine the therapeutic target molecule(s). Design and method: First, the difference in skeletal muscles in the lower leg between WKY and SHRSP was evaluated mainly through weight/tibial length and histological analysis. Further experiments were carried out based on gene expression using microarray, protein expression, and immunohistochemistry analyses. Results: SHRSP had a significantly lower weight/tibial length in the soleus and gastrocnemius, but not in the plantaris and tibialis anterior. This suggests that muscles with a relatively high amount of slow muscle fiber (type I fiber) show hypotrophy. Histological analysis of the soleus, showing that type I fibers mainly decreased the fiber size, corresponded to the result of weight/tibial length. Microarray and protein expression analyses showed that the muscle-specific ubiquitin ligase, muscle RING finger 1 (MuRF1), but not atrogin-1, was highly expressed in the soleus, but not in the plantaris, in SHRSP. TNF-like weak inducer of apoptosis receptor (TWEAKR) was predicted as a MuRF1 up-regulator in the Ingenuity Pathway Analysis. There was no significant difference in TWEAKR expression level in the soleus between WKY and SHRSP. However, immunofluorescence revealed that WKY had only type II fiber staining, but SHRSP had both type I and II fiber staining. Conclusions: TWEAKR is a type II-specific receptor in the skeletal muscle. Ectopic TWEAKR expression in type I fibers of SHRSP is most likely involved in slow muscle-specific hypotrophy through MuRF1 overexpression. The TWEAKR-MuRF1 pathway may be a useful therapeutic target for slow muscle hypotrophy.