34 research outputs found
The proton pump inhibitor lansoprazole improves the skeletal phenotype in dystrophin deficient mdx mice
Background
In Duchenne muscular dystrophy (DMD), loss of the membrane stabilizing protein dystrophin results in myofiber damage. Microinjury to dystrophic myofibers also causes secondary imbalances in sarcolemmic ion permeability and resting membrane potential, which modifies excitation-contraction coupling and increases proinflammatory/apoptotic signaling cascades. Although glucocorticoids remain the standard of care for the treatment of DMD, there is a need to investigate the efficacy of other pharmacological agents targeting the involvement of imbalances in ion flux on dystrophic pathology. Methodology/Principal Findings
We designed a preclinical trial to investigate the effects of lansoprazole (LANZO) administration, a proton pump inhibitor, on the dystrophic muscle phenotype in dystrophin deficient (mdx) mice. Eight to ten week-old female mice were assigned to one of four treatment groups (n = 12 per group): (1) vehicle control; (2) 5 mg/kg/day LANZO; (3) 5 mg/kg/day prednisolone; and (4) combined treatment of 5 mg/kg/day prednisolone (PRED) and 5 mg/kg/day LANZO. Treatment was administered orally 5 d/wk for 3 months. At the end of the study, behavioral (Digiscan) and functional outcomes (grip strength and Rotarod) were assessed prior to sacrifice. After sacrifice, body, tissue and organ masses, muscle histology,in vitro muscle force, and creatine kinase levels were measured. Mice in the combined treatment groups displayed significant reductions in the number of degenerating muscle fibers and number of inflammatory foci per muscle field relative to vehicle control. Additionally, mice in the combined treatment group displayed less of a decline in normalized forelimb and hindlimb grip strength and declines in in vitro EDL force after repeated eccentric contractions. Conclusions/Significance
Together our findings suggest that combined treatment of LANZO and prednisolone attenuates some components of dystrophic pathology in mdx mice. Our findings warrant future investigation of the clinical efficacy of LANZO and prednisolone combined treatment regimens in dystrophic pathology
Osteopontin is linked with AKT, FoxO1, and myostatin in skeletal muscle cells
Introduction: Osteopontin (OPN) polymorphisms are associated with muscle size and modify disease progression in Duchenne muscular dystrophy (DMD). We hypothesized that OPN may share a molecular network with myostatin (MSTN).
Methods: Studies were conducted in the golden retriever (GRMD) and mdx mouse models of DMD. Follow-up in-vitro studies were employed in myogenic cells and the mdx mouse treated with recombinant mouse (rm) or human (Hu) OPN protein.
Results: OPN was increased and MSTN was decreased and levels correlated inversely in GRMD hypertrophied muscle. RM-OPN treatment led to induced AKT1 and FoxO1 phosphorylation, microRNA-486 modulation, and decreased MSTN. An AKT1 inhibitor blocked these effects, whereas an RGD-mutant OPN protein and an RGDS blocking peptide showed similar effects to the AKT inhibitor. RMOPN induced myotube hypertrophy and minimal Feret diameter in mdx muscle. Discussion: OPN may interact with AKT1/MSTN/FoxO1 to modify normal and dystrophic muscle
Genetic Characterization of Physical Activity Behaviours in University Students Enrolled in Kinesiology Degree Programs
Studies of physical activity behaviours have increasingly shown the importance of heritable factors such as genetic variation. Non-synonymous polymorphisms of alpha-actinin 3 (ACTN3) and the ĂË-adrenergic receptors 1 and 3 (ADRB) have been previously associated with exercise capacity and cardiometabolic health. We thus hypothesized that these polymorphisms are also related to physical activity behaviors in young adults. To test this hypothesis we examined relationships between ACTN3 (R577X), ARDB1 (Arg389Gly) and ADRB3 (Trp64Arg), and physical activity behaviors in university students. We stratified for student enrollment in kinesiology degree programs compared to non-majors as we previously found this to be a predictor of physical activity. We did not identify novel associations between physical activity and ACTN3. However, the minor alleles of ADRB1 and ADRB3 were significantly underrepresented in kinesiology students compared to non-majors. Furthermore, carriers of the ADRB1 minor allele reported reduced participation in moderate physical activity and increased afternoon fatigue compared to ancestral allele homozygotes. Together, these findings suggest that the heritability of physical activity behaviours in young adults may be linked to non-synonymous polymorphisms within ĂË-adrenergic receptors.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author
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Physiological Adaptations to Progressive Endurance Exercise Training in Adult and Aged Rats: Insights from the Molecular Transducers of Physical Activity Consortium (MoTrPAC)
While regular physical activity is a cornerstone of health, wellness, and vitality, the impact of endurance exercise training on molecular signaling within and across tissues remains to be delineated. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to characterize molecular networks underlying the adaptive response to exercise. Here, we describe the endurance exercise training studies undertaken by the Preclinical Animal Sites Studies component of MoTrPAC, in which we sought to develop and implement a standardized endurance exercise protocol in a large cohort of rats. To this end, Adult (6-mo) and Aged (18-mo) female (n = 151) and male (n = 143) Fischer 344 rats were subjected to progressive treadmill training (5 d/wk, âŒ70%-75% VO2max) for 1, 2, 4, or 8 wk; sedentary rats were studied as the control group. A total of 18 solid tissues, as well as blood, plasma, and feces, were collected to establish a publicly accessible biorepository and for extensive omics-based analyses by MoTrPAC. Treadmill training was highly effective, with robust improvements in skeletal muscle citrate synthase activity in as little as 1-2 wk and improvements in maximum run speed and maximal oxygen uptake by 4-8 wk. For body mass and composition, notable age- and sex-dependent responses were observed. This work in mature, treadmill-trained rats represents the most comprehensive and publicly accessible tissue biorepository, to date, and provides an unprecedented resource for studying temporal-, sex-, and age-specific responses to endurance exercise training in a preclinical rat model
Montmorency Cherry Juice Consumption does not Improve Muscle Soreness or Inhibit Pro-inflammatory Monocyte Responses Following an Acute Bout of Whole-body Resistance Training.
International Journal of Exercise Science 15(6): 686-701, 2022. Montmorency Cherry Juice (MCJ) may improve acute exercise recovery by attenuating inflammation and oxidative stress. However, the anti-inflammatory effects of MCJ on monocyte responses following resistance exercise have not been explored. Seven resistance-trained males (age: 22.9 ± 4.1 yrs; height: 1.8 ± 0.1 m; weight: 81.7 ± 13.2 kg) participated in this study. Participants completed a placebo-controlled crossover design, drinking either MCJ or placebo beverages, 7 days prior to completing an acute bout of unilateral resistance exercise. Statistical significance was assessed using a within-subjects repeated measures ANOVA; alpha level p †0.05. Main effects for time were observed for changes in classical and intermediate monocytes (p †0.05), but no significant treatment effects were observed for monocyte subtypes p \u3e 0.05. Classical monocytes (CD14+ CD16-) increased and peaked 24 hr post-exercise (placebo 1.14 ± 0.04 and MCJ 1.06 ± 0.06-fold). Intermediate monocytes peaked 48 hr post-exercise increasing 1.82 ± 0.41 and 2.01 ± 0.80-fold. Nonclassical monocytes peaked post-exercise (placebo 1.17 ± 0.31 and MCJ 1.02 ± 0.20-fold). Peak pain visual analog scale (VAS) occurred post-exercise for MCJ (3.63 ± 2.01-fold) and 72 hr post-exercise for placebo (4.26 ± 3.46-fold). IL-6 and pressure pain threshold (PPT) peaked 24 hr post-exercise (IL-6 placebo 3.83 ± 1.01- and MCJ 6.43 ± 3.43-fold) and (PPT placebo 86.37 ± 3.95% and MCJ 82.81 ± 2.90% of pressure needed at pre-exercise). Our data suggests MCJ consumption does not decrease muscle soreness, IL-6, or monocyte subset responses following a high-intensity resistance exercise protocol in resistance-trained males
The proton pump inhibitor lansoprazole improves the skeletal phenotype in dystrophin deficient mdx mice.
In Duchenne muscular dystrophy (DMD), loss of the membrane stabilizing protein dystrophin results in myofiber damage. Microinjury to dystrophic myofibers also causes secondary imbalances in sarcolemmic ion permeability and resting membrane potential, which modifies excitation-contraction coupling and increases proinflammatory/apoptotic signaling cascades. Although glucocorticoids remain the standard of care for the treatment of DMD, there is a need to investigate the efficacy of other pharmacological agents targeting the involvement of imbalances in ion flux on dystrophic pathology.We designed a preclinical trial to investigate the effects of lansoprazole (LANZO) administration, a proton pump inhibitor, on the dystrophic muscle phenotype in dystrophin deficient (mdx) mice. Eight to ten week-old female mice were assigned to one of four treatment groups (nâ=â12 per group): (1) vehicle control; (2) 5 mg/kg/day LANZO; (3) 5 mg/kg/day prednisolone; and (4) combined treatment of 5 mg/kg/day prednisolone (PRED) and 5 mg/kg/day LANZO. Treatment was administered orally 5 d/wk for 3 months. At the end of the study, behavioral (Digiscan) and functional outcomes (grip strength and Rotarod) were assessed prior to sacrifice. After sacrifice, body, tissue and organ masses, muscle histology, in vitro muscle force, and creatine kinase levels were measured. Mice in the combined treatment groups displayed significant reductions in the number of degenerating muscle fibers and number of inflammatory foci per muscle field relative to vehicle control. Additionally, mice in the combined treatment group displayed less of a decline in normalized forelimb and hindlimb grip strength and declines in in vitro EDL force after repeated eccentric contractions.Together our findings suggest that combined treatment of LANZO and prednisolone attenuates some components of dystrophic pathology in mdx mice. Our findings warrant future investigation of the clinical efficacy of LANZO and prednisolone combined treatment regimens in dystrophic pathology
OPN-a induces muscle inflammation by increasing recruitment and activation of pro-inflammatory macrophages.
New Findings What is the central question of this study? What is the functional relevance of OPN isoform expression in muscle pathology? What is the main finding and its importance? The fullâlength human OPNâa isoform is the most proâinflammatory isoform in the muscle microenvironment, acting on macrophages and myoblasts in an RGDâintegrinâdependent manner. OPNâa upregulates expression of tenascinâC (TNC), a known Tollâlike receptor 4 (TLR4) agonist. Blocking TLR4 signalling inhibits the proâinflammatory effects of OPNâa, suggesting that a potential mechanism of OPN action is by promoting TNCâTLR4 signalling. Although osteopontin (OPN) is an important mediator of muscle remodelling in health and disease, functional differences in human spliced OPN variants in the muscle microenvironment have not been characterized. We thus sought to define the proâinflammatory activities of human OPN isoforms (OPNâa, OPNâb and OPNâc) on cells present in regenerating muscle. OPN transcripts were quantified in normal and dystrophic human and dog muscle. Human macrophages and myoblasts were stimulated with recombinant human OPN protein isoforms, and cytokine mRNA and protein induction was assayed. OPN isoforms were greatly increased in dystrophic human (OPNâa \u3e OPNâb \u3e OPNâc) and dog muscle (OPNâa = OPNâc). In healthy human muscle, mechanical loading also upregulated OPNâa expression (eightfold; P \u3c 0.01), but did not significantly upregulate OPNâc expression (twofold; P \u3e 0.05). In vitro, OPNâa displayed the most pronounced proâinflammatory activity among isoforms, acting on both macrophages and myoblasts. In vitro and in vivo data revealed that OPNâa upregulated tenascinâC (TNC), a known Tollâlike receptor 4 (TLR4) agonist. Inhibition of TLR4 signalling attenuated OPNâmediated macrophage cytokine production. In summary, OPNâa is the most abundant and functionally active human spliced isoform in the skeletal muscle microenvironment. Here, OPNâa promotes proâinflammatory signalling in both macrophages and myoblasts, possibly through induction of TNCâTLR4 signalling. Together, our findings suggest that specific targeting of OPNâa and/or TNC signalling in the damaged muscle microenvironment may be of therapeutic relevance