bluuebunny/crossref_metadata_2025 huggingface dataset:
Impairment in evoked V‐wave response during maximal muscle contraction in subjects with Parkinson's disease
Authors: Silva‐Batista Carla , Mattos Eugenia , Corcos Daniel , David Fabian , Kanegusuku Hélcio , Forjaz Claudia , Tricoli Valmor , Roschel Hamilton , Ugrinowitsch Carlos
Published: November 2023

Introduction

Reduced descending drive to muscle, when assessed by V‐wave, is attenuated in aging. In subjects with Parkinson's disease (PD) it can be more reduced and associated with motor signs, however, it was still not investigated.

Objective

To compare evoked reflex at rest and during maximal voluntary isometric contraction (MVIC) of the plantar flexors in subjects with PD and age‐matched healthy controls (HC). It also investigated association between PD motor signs and maximal V wave‐to‐maximal M wave (V/Mmax) ratio.

Methods

Evoked reflex at rest (H‐reflex and M‐wave amplitudes) and root mean square (RMS), peak torque (PT), and evoked reflex (V‐wave and M‐wave amplitudes) during MVIC were recorded in 10 subjects with PD (64.9 ± 9.4 years, 12.4 ± 5.8 disease duration, 41.8 ± 10.3 motor severity, 2.6 ± 0.4 stage of PD) and 10 HC (64.8 ± 9.3 years). The subjects with PD were assessed in the clinically “on” state.

Results

At rest, maximal H wave‐to‐maximal M wave (Hmax/Mmax) ratio was not different between groups (P=0.060) while during MVIC, RMS, PT, V‐wave, M‐wave, and V/Mmax ratio were lower for subjects with PD (P<0.05). There was association between PD motor signs and V/Mmax ratio (r=−0.73, 95% confidence interval = −0.93 to −0.19, P=0.015).

Conclusions

Subjects with PD present reduced amplitude in V‐wave and impairment in V/Mmax ratio, which is associated with motor signs, likely due to abnormal descending drive to muscle that reflects a decrease of supraspinal activation.

Support or Funding Information

Financial support: FAPESP: 2013/04970‐4 and CNPq: 406609/2015‐2.
Lower Percent Leg Muscle Mass is Associated with Reduced Ventilatory Efficiency in Sedentary Adults
Authors: Keller‐Ross Manda L , Chantigian Daniel P , Evanoff Nick , Bosch Tyler , Bantle Anne , Dengel Donald , Chow Lisa
Published: November 2023

A high ventilatory equivalent to carbon dioxide production (VE/VCO2) slope, or reduced ventilatory efficiency, is associated with disease severity and is a strong predictor of mortality in patients with heart failure (HF). We have demonstrated that a high VE/VCO2 slope during exercise is associated with lower %leg muscle mass in HF. This association was abolished with inhibition of skeletal muscle afferent feedback by lumbar fentanyl injections, demonstrating an important link between muscle mass, afferent feedback and VE/VCO2 slope. We hypothesized that %leg muscle mass would be associated with VE/VCO2 slope in sedentary adults.

Objective

Determine the relationship between %leg muscle mass and VE/VCO2 slope in sedentary (SED) and trained (TR) adults.

Methods

For 38 adults (23 SED [6M/17F], 31±8 yrs and 15 TR [9M/6F], 29±6 yrs (mean±SD)) measures of gas exchange and ventilation were collected during a treadmill maximal oxygen uptake (VO2max) test and measures of total fat, regional fat and muscle mass were done by dual X‐ray absorptiometry (DXA). Participants were classified as trained by self‐report of aerobic exercise training for at least 30 min/day, 5 days/week.

Results

In the SED group, men had greater %leg muscle mass and VO2max, and less %leg fat mass than women (all p<0.05). In the TR group, VO2max and %leg fat were similar (p>0.05), but men had greater %leg muscle mass than women (p<0.05). Percent leg muscle mass was greater in TR than SED (80±8 vs. 58±9%, respectively, p<0.01), while %leg fat mass was lower in TR than SED (20±9 vs. 42±9%, respectively, p<0.01). VO2max was greater in TR than SED (55±10 vs. 29±6 ml/kg/min, p<0.01). When the TR and SED groups were combined, VO2max was associated with %leg muscle mass (r= 0.85, p<0.01). The VE/VCO2 slope was similar between TR and SED groups (25±3 vs. 24±3, p=0.10), without any sex‐specific differences (p>0.05). Specific to the SED group, VE/VCO2 slope was inversely associated with %leg muscle mass (r= −0.51, p=0.01) indicating the lower the %leg muscle mass, the steeper the VE/VCO2 slope. This relationship persisted with sex‐specific analysis (men: r= −0.80, p=0.05 and women: r= −0.57, p=0.02). The relationship between VE/VCO2 slope and %leg muscle mass not was not observed in the TR group overall or with sex‐specific analysis (p>0.05).

Conclusions

These findings suggest that in sedentary adults, lower %leg muscle mass may contribute to a reduced ventilatory efficiency during exercise.

Support or Funding Information

NIH 1R01DK098203‐01
A 14 Day Recovery Period Reverses the Decline in Lifelong Physical Activity Following a Significant Ankle Sprain
Authors: Hubbard‐Turner Tricia , Wikstrom Erik A , Turner Michael J
Published: November 2023

We have previously shown a decrease in lifelong physical activity following a significant ankle sprain in mice. To investigate the impact of a prolonged rest period on lifelong activity, at seven weeks of age we transected the CFL and ATFL of the right hindlimb in six male CBA/J mice and conducted a SHAM surgery on 10 male CBA/J mice. The SHAM mice were placed in separate cages with a running wheel immediately post‐surgery while the ankle sprain (AS) mice were placed in separate cages but exposed to a running wheel 14 days post‐surgery to allow for tissue healing. Physical activity was measured daily from eight weeks until 52 weeks of age (72% of lifespan). Daily duration, distance and running speed were analyzed by ANOVA (Group × Time) with repeated measures (p<0.05) at 15‐week periods to approximate the first three quartiles of lifespan. From weeks three to 15 post‐surgery, duration and distance were not different between groups but the running speed was faster for the SHAM mice (p=0.009). No differences were observed between groups for duration, distance or running speed from weeks 16 to 30 or 31 to 45 post‐surgery (p>0.05). Additionally, duration, distance, and running speed did not significantly change across/among the 15‐week periods. These findings suggest the commonly observed decline in physical activity throughout the lifespan following an ankle sprain can be restored to non‐injured levels with the incorporation of a 14 day rest period in mice.

Support or Funding Information

Supported by UNC Charlotte Faculty Research Grants (Hubbard‐Turner, Wikstrom, and Turner)
Differentiated contribution of fat pads to the prevention of insulin resistance through aerobic exercise training
Authors: Américo Anna Laura Viacava , Muller Cynthia Rodrigues , Fonseca‐Alaniz Miriam Helena , Evangelista Fabiana Sant'Anna
Published: November 2023

Increased white adipose tissue (WAT) is associated with the development of insulin resistance (IR), and this response may be due to impaired insulin signaling caused by excess of lipids. Aerobic exercise training (AET) prevents IR by improving lipid oxidation and glucose metabolism. Here we evaluated the relative contribution of fat pads to the prevention of IR through AET. Adult male C57BL6/J mice were assigned into chow‐fed controls (C, n=5), cafeteria diet (CAF, n=5), chow‐fed trained (T, n=5), and cafeteria diet plus trained (CAFT, n=5). AET was performed simultaneously with diet and consisted of 8‐wk running session of 60 min at 60% of maximal speed, 5 days/wk. Experimental procedures were approved by Ethics Committee from Faculty of Medicine of University of São Paulo (# 002/15). The body weight of T and CAFT groups were lower from the third week of experimental protocol compared to C. The CAF group had higher retroperitoneal (RP) and subcutaneous (SC) WAT weights compared to C, but the AET was able to prevent these increases in CAFT group. The T group presented lower periepididimal (PE) WAT compared to other groups, but interscapular BAT weight did not differ among groups. Cafeteria diet induced glucose intolerance and IR in CAF group (AUC: 35200± 1076 mg/dL/120min; kITT: 2,5 ± 0,17 %/min, respectively) compared to C group (AUC: 28333±1305 mg/dL/120min; kITT:, 3,7 ± 0,21 %/min respectively) during glucose and insulin tolerance tests, respectively, which were counteracted by AET in CAFT group (AUC: 28896 ± 1133 mg/dL/120min; kITT: 3,9 ± 0,33 %/min, respectively). Protein expressions of GLUT‐4 and t‐AKT were not different among groups, but p‐AKT reduced in T, CAF and CAFT groups compared to C in the PE‐WAT, and the p‐AKT/t‐AKT ratio was lower in CAFT compared to C in SC‐WAT. There were no differences in t‐AMPK and p‐AMPK expressions in SC‐WAT, but increase in t‐AMPK and p‐AMPK in T and CAFT groups compared to C and CAF groups in PE‐WAT. Histological analysis of the SC‐WAT showed the presence of multilocular adipocytes agglometares in T and CAFT groups, which is typical of WAT browning. In conclusion, the prevention of IR by AET is associated with lower visceral and subcutaneous WAT deposition, changes in the expression of metabolic proteins in PE‐WAT, such as reduction in p‐AKT and increase in t‐AMPK and p‐AMPK, and browning in the SC‐WAT.

Support or Funding Information

FAPESP # 2015/04948‐4.
Physical Activity Following A 14 Day Recovery Period Was Greater In Aging CBA/J Mice After A Significant Ankle Sprain
Authors: Turner Michael J. , Wikstrom Erik A. , Hubbard‐Turner Tricia
Published: November 2023

A significant lateral ankle sprain results in a decrease in lifelong physical activity, with increased likelihood for chronic disease development. To investigate the impact of different rest periods on lifelong activity, we transected the CFL and ATFL of the right hindlimb in 18 male CBA/J mice at seven weeks old. Each mouse was placed in separate cages and randomized into three groups of six mice and received a running wheel three days (3D), seven days (7D) or 14 days (14D) post‐surgery. Physical activity was measured daily from eight weeks until 52 weeks of age (72% of lifespan). Daily duration, distance and running speed were analyzed by ANOVA (Group × Time) with repeated measures (p<0.05) at 15‐week periods to approximate the first three quartiles of lifespan. From weeks three to 15 post‐surgery, duration, distance, and running speed were not different between groups, but all activity variables increased with time (p<0.05). From weeks 16 to 30 post‐surgery, distance (p=0.041) and running speed (p=0.010) were greater in the 14D group compared to 3D and 7D, while duration was not different among the groups (p=0.185). There were no differences with time from 16 to 30 weeks (p<0.05). From weeks 31 to 45 post‐surgery, duration (p=0.020), distance (p=0.009) and running speed (p=0.007) were greater in the 14D group compared to 3D and 7D. No differences were found with time from 31 to 45 weeks (p>0.05). Our findings suggest the longer rest period of 14 days following a lateral ankle sprain can significantly increase activity levels (duration, distance and running speed) throughout the second and third quartile of life.

Support or Funding Information

Supported by UNC Charlotte Faculty Research Grants (Turner, Wikstrom, and Hubbard‐Turner).
No Evidence for Soleus Muscle Capillary Involution or Neogenesis in Rats with Prostate Cancer
Authors: Opoku‐Acheampong Alexander Boadu , Esau Peter John , Poole David Christopher , Gittemeier Elizabeth Marie , Copp Steven Wesley , Behnke Bradley Jon
Published: November 2023

Capillarity in skeletal muscle is crucial for achieving effective blood‐muscle oxygen (O2) flux and can be impacted by multiple conditions including exercise training (↑), forced inactivity (e.g., bedrest) (↓) and chronic disease (↓). However, it is unknown whether prostate cancer alters skeletal muscle capillarity. In particular the capillary‐to‐fiber ratio represents a sensitive index of capillary neogenesis/involution in skeletal muscle. We examined capillarity in the soleus muscle of ~8‐month‐old male sham operated (CON, n = 7) and orthotopic prostate tumor (PT)‐bearing Copenhagen rats (Dunning R‐3327‐AT1 tumor cells; n = 9). Eight weeks post‐surgery, soleus muscles were excised and frozen rapidly. Eight μm sections were cut transverse to the principle fiber axis, stained with lectin and examined with a fluorescence microscope (at 470× magnification). Capillaries around the fibers, capillary density, capillary‐to‐fiber ratio, fiber cross‐sectional area, and sharing index were measured directly from images of soleus sections using standard point‐counting techniques adhering to strict non‐biased morphometric principles. Body weight, soleus weight, and soleus muscle citrate synthase activity were not impacted by the prostate cancer (tumor weight, 9.8 ± 2.6 g). There was no difference between CON and PT for capillary‐to‐fiber ratio (2.2 ± 0.1 vs. 2.3 ± 0.1), capillaries around fiber (4.3 ± 0.1 vs. 4.4 ± 0.1), capillary density (388 ± 16 vs. 403 ± 28 cap./mm2), sharing index (1.9 ± 0.1 vs. 2.0 ± 0.1), nor fiber cross‐sectional area (5815 ± 270 vs. 6005 ± 515 μm2) (all p > 0.05). In conclusion, prostate cancer did not significantly affect these aspects of two‐dimensional capillary or capillary‐to‐fiber geometry in the soleus muscle. How prostate cancer impacts hemodynamics, red blood cell distribution and blood‐myocyte O2 flux within these capillaries at rest and during exercise and whether this contributes to the physiological dysfunction of prostate cancer patients remains a crucial question.

Support or Funding Information

American Cancer Society RSG‐14‐150‐01‐CCE
Sex‐Related Differences in Reactivity of Cerebral Arterioles During Moderate Exercise Training
Authors: Arrick Denise M , Li Chun , Mayhan William
Published: November 2023

Background

The goals of our study were to determine the influence of sex on reactivity of cerebral arterioles and whether moderate exercise training (MExT) could influence sex‐related differences in reactivity of cerebral arterioles.

Methods

Responses of cerebral arterioles were measured in Sedentary (Sed) and MExT adult male and female Sprague‐Dawley rats to eNOS‐dependent (ADP); nNOS‐dependent (NMDA) and NOS‐independent (nitroglycerin) agonists before and following L‐NMMA. In addition, protein expression for eNOS and nNOS was determined.

Results

We found that NOS‐dependent vasodilation was enhanced in Sed and MExT female rats compared to their male counterparts. L‐NMMA produced a greater decrease in baseline diameter of arterioles in females compared to males, and produced less inhibition of NOS‐dependent vasodilation in females. Expression of eNOS protein was significantly increased in Sed female when compared to Sed male rats, nNOS protein was similar in Sed males and females, but increased in MExT females.

Conclusions

These findings indicate that while NOS‐dependent vascular reactivity is increased in females, MExT does not alter vasodilation in males or females. These studies provide insights into the influence of sex and MExT on the cerebral microcirculation and may have implications regarding mechanisms that protect the brain in females compared to males during disease states.
Autophagy is Independent of Disease Progression in the Dystrophic Myocardium in Mouse and Porcine Dystrophinopathy Models
Authors: Spaulding Hannah , Nonneman Dan , Ross Jason , Selsby Joshua
Published: November 2023

Dystrophinopathies are muscle diseases caused by mutations in the dystrophin gene resulting in insufficiency or absence of functional dystrophin protein. A deficiency of functional dystrophin results in membrane instability, mitochondrial dysfunction and metabolic abnormalities. Autophagy functions to remove damaged organelles, proteins and other cellular components and is emerging as an important process in dystrophic skeletal muscle, though the role of autophagy in dystrophic myocardium is currently unknown. The purpose of this investigation is to determine the extent to which autophagy is affected by disease progression in cardiac muscle. We hypothesized that dystrophin deficiency would result in progressive autophagic dysfunction in the heart. To address this hypothesis protein abundances from 7 week and 17 months old mdx mice were compared to C57 age‐matched controls. Surprisingly, measures of autophagic initiation, phosphorylated AMPK T172, phosphorylated UNC‐51‐like kinase 1 (ULK1) and Beclin‐1, were similar between all groups. In addition, autophagy‐related gene 5 (ATG5) and the ATG 12/5 complex, proteins indicative of autophagosome formation, were similar between groups. Furthermore, LC3I and the LC3I lipidation product, LC3II, were similar to age‐matched controls and markers of autophagic flux, the LC3II/I ratio and p62, were also similar between groups. To confirm that autophagy was independent of disease progression, heart tissue from a novel porcine dystrophinopathy model was also evaluated. Hearts were collected from healthy and affected male littermates at 3 and 12 months of age. This porcine model is dystrophin insufficient with necrotic lesions apparent at 12 months but not at 3 months of age. Consistent with our findings in the mdx mouse, protein abundances of phosphorylated ULK1, Beclin, ATG12/5 complex formation, LC3I, and p62 were similar between all groups. LC3II and the LC3II/I ratio were decreased as a function of age but did not differ with dystrophin deficiency. These data suggest that disease progression does not cause autophagic dysfunction in dystrophic myocardium.

Support or Funding Information

This work was supported in part by NIH R21 NS079603 and the Duchenne Alliance.
Blood Pressure Responses at Exercise Onset in Postmenopausal Women
Authors: Duggal Divya , Matthews Evan L , Greaney Jody L , Wenner Megan M
Published: November 2023

Exaggerated blood pressure (BP) responses at exercise onset may be characteristic of several cardiovascular diseases (CVD). Primary aging is a risk factor for CVD, and after menopause the prevalence of CVD is greater in postmenopausal women (PMW). Therefore, the purpose of this study was to test the hypothesis that BP responses at exercise onset are exaggerated in normotensive PMW compared to young women (YW). We retrospectively analyzed beat‐by‐beat BP and heart rate (HR) in 15 PMW (59±1yrs, 25±1kg•m2) and 16 young women (22±1yrs, 22±1kg•m2) in 10‐second intervals at the onset of isometric handgrip exercise at 30% of maximal voluntary contraction. Resting mean arterial BP (PMW: 87±3, YW: 84±3 mmHg, P>0.05) and HR (PMW: 62±2, YW: 66±2 bpm, P>0.05) were similar between groups. Systolic BP increased more in PMW (P<0.05), and tended to be higher at 30s of isometric exercise (PMW: Δ9±2 vs. YW: Δ5±1 mmHg, P=0.06). Mean arterial BP also tended to increase more in PMW (ANOVA P=0.12), whereas diastolic BP and HR responses were similar between groups (P>0.05). In conclusion, exaggerated BP responses at exercise onset may be associated with age and menopause.

Support or Funding Information

Research supported by NIH Grant U54‐GM104941 and P20‐GM113125
Effects of aging and treadmill exercise on cognitive function and the expression of BDNF in the hippocampus
Authors: Maejima Hiroshi , Kanemura Naohiko , Kokubun Takanori , Murata Kenji , Takayanagi Kiyomi
Published: November 2023

Neurotrophins play a crucial role in neuroplasticity, neurogenesis, and neuroprotection in the central nervous system. Aerobic exercise is known to increase the expression of brain‐derived neurotrophic factor (BDNF) in the hippocampus. The objective of this study was to investigate the effects of aging and moderate exercise on cognitive function and the expression of BDNF in the hippocampus using senescence‐accelerated mouse P1 (SAMP1) and its age‐matched control mouse (SAMR1).

13‐month‐old SAMR1 and SAMP1 mice were randomly distributed to four groups based on two factors comprising accelerated aging (SAMR1 versus SAMP1) and exercise (sedentary versus exercise), i.e. SAMR1 sedentary group (R1‐Sed), SAMR1 exercise group (R1‐Ex), SAMP1 csedentary group (P1‐Con) and SAMP1 exercise group (P1‐Ex). The exercised mice performed moderate treadmill exercise (12 m/min, 60 min) five times a week for four weeks. After four week intervention, the novel‐object recognition test was performed to evaluate recognition memory. The expression of mRNA and protein abundance of neurotrophins of BDNF in the hippocampus was assayed using Real time PCR and ELISA. A two‐way analysis of variance (ANOVA) was performed for each analysis to investigate the effects of accelerated aging (R1 versus P1) and exercise (sedentary versus exercise), as well as two‐factor interaction. All study procedures were approved by the ethics committee for animal research of Saitama Prefectural University in Japan and conducted according to the guidelines of the committee.

A two‐way ANOVA showed a significant factorial effect of exercise and no significant interaction in the score of the novel‐object recognition test, the expression of mRNA and protein abundance of BDNF, demonstrating that the exercise improved the recognition memory and up‐regulated the expression of BDNF similarly in SAMR1 and SAMP1. This study elucidated the beneficial effects of the moderate exercise on the expression of BDNF in SAMP1 as well as in SAMR1, suggesting that moderate exercise could contribute to protect the degeneration of cognitive function in the elderly through the up‐regulation of BDNF expression in the hippocampus.

Support or Funding Information

This work was supported by JSPS KAKENHI Grant 21500471.
The Effect of Exercise Pattern on Insulin Responses in Healthy, Young Males
Authors: Castleberry Todd , Ramirez Joel , Deemer Sarah E , Irvine Christopher , Rouwtt De'Andrea , Oldham Michael , Ben‐Ezra Vic
Published: November 2023

BACKGROUND

It is often reported that a single bout of exercise lowers insulin responses 12–24 hours post exercise. It is not known if alternate or consecutive days of exercise have an additive effect on insulin responses. Our hypothesis is that both alternate and consecutive days of exercise will improve insulin responses/glucose control more than a single bout of exercise.

PURPOSE

The purpose of this study was to examine the effect of exercise pattern on post‐exercise insulin and glucose responses to a glucose challenge.

METHODS

Eleven healthy adult male participants (n=11, mean ± SD, 28.6 ± 7.9 yrs; BMI: 25.7 ± 2.8 kg/m2, VO2max; 38.7 ± 4.7 ml/kg/min; fasting plasma glucose: 4.85 mmol/l; fasting plasma insulin: 8.4 μU/ml) completed three submaximal exercise trials of walking on a treadmill for 60 minutes at ~70% of VO2max. The trials consisted of: 3 consecutive exercise days (3CON), 3 alternate exercise days (3ALT), a single bout of exercise (SB), and a no exercise control (R). In the morning, 12–14 hours after the last bout of exercise or R, participants completed a 75g oral glucose tolerance test and blood was collected at 0, 30, 60, 90, 120, and 150 minutes for the measurement of glucose, insulin, and C‐peptide. Glucose was analyzed using enzyme electrode technology (YSI 2900) and insulin and C‐peptide were measured via ELISA. A one‐way repeated measures ANOVA with a Bonferroni post hoc was used for statistical analysis. Diet logs were kept throughout each trial to ensure consistency for all participants.

RESULTS

Calculated integrated area under the curve (iAUC) for glucose and C‐peptide was not different between the 4 trials. Insulin iAUC was significantly decreased 33.9% for 3CON compared to R (p=0.006). Insulin iAUC decreased for SB (8.4%) and 3ALT (24.1%) compared to R, however these values did not reach statistical significance.

CONCLUSION

Three consecutive days of walking at ~70% VO2max improved insulin response to a 75g glucose load compared to no exercise. Interestingly, a single bout of exercise and three alternate days of exercise did not significantly improve insulin responses compared to no exercise. It is possible, that for healthy, young males, the response to a single bout of exercise, or exercise bouts separated by more than 24 hours may not be enough stimulus to improve insulin responses.
Post‐effects of walking intensity on cardiovascular function and autonomic regulation in patients with intermittent claudication
Authors: Chehuen Marcel , Lima Aluisio H. , Silva Natan Daniel , Costa Luiz Augusto Riani , Miyasato Roberto Sanches , Wolosker Nelson , Forjaz Cláudia
Published: November 2023

Introduction

Patients with intermittent claudication (IC) exhibit limited walking capacity and often present cardiovascular alterations, such as high blood pressure (BP), endothelial dysfunction and cardiac autonomic dysfunction. Walking training is recommended to these individuals to improve walking capacity, and some authors suggest that maximal walking (until maximal pain) may be more effective than submaximal walking. An acute submaximal walking session has been shown to promote post‐exercise hypotension, while the effect of maximal walking on this parameter is unknown.

Objective

To compare the acute post‐effect of submaximal and maximal walking on cardiovascular function and autonomic regulation in patients with IC.

Methods

Thirty patients with IC (66 ± 11 years) underwent two experimental session: one submaximal (15 bouts of 2 min of walking at the heart rate (HR) of pain threshold interpolated by 2 min of upright rest) and one maximal (walking at 2 mph with 2% increase in grade every 2 min until maximal leg pain). HR (ECG), BP (auscultatory), rate pressure product (RPP), resting and after reactive hyperemia blood flow (BF) (plethysmography), and low (LF) and high (HF) frequency components of HR variability were measured before and 30 minutes after the walking protocols. A 2‐way ANOVA for repeated measures was used (P<0.05).

Results

In comparison with the pre‐exercise values, systolic and mean BP decreased and diastolic BP did not change after the submaximal walking, while these BPs increased after the maximal walking (−7±7 vs. +5±7, −3±3 vs. +5±5 and 0±3 vs. +5±4 mmHg, respectively). HR increased similarly after the submaximal and the maximal walking (+3±4 vs. +3±6 bpm, respectively), while RPP did not change after the submaximal, but increased after the maximal walking (−158±645 vs. +752±791 mmHg*bpm). Resting forearm and leg BF (+0.24±0.22 vs. +0.27±0.22 and +0.78±0.79 vs. +0.66±1.03 ml.100ml tissue−1.min−1, respectively) as well as forearm BF after reactive hyperemia (+1.7±4.5 vs. +2.2±3.9 ml.100ml tissue−1.min−1, respectively) increased similarly after the submaximal and maximal walking, while leg BF after reactive hyperemia did not change after any session (0.0±3.5 vs. −0.1±2.6 ml.100ml tissue−1.min−1, respectively). LF increased, HF decreased and LF/HF increased similarly after the submaximal and the maximal walking (+8±21 vs. +9±20 nu; −9±17 vs. −10±20 nu and 0.2±0.4 vs. 0.2±0.5, respectively).

Conclusion

In patients with IC, an acute submaximal but not maximal walking session promotes post‐exercise hypotension; while cardiac work (RPP) increases only after maximal walking. On the other hand, BF, vasodilation, HR and cardiac sympathovagal modulation increases after both maximal and submaximal walking.

Support or Funding Information

Financial support: CNPQ e FAPESP.
Angiotensin‐II Rapidly Decreases MiR‐23a and MiR‐182 in Muscle Cells
Authors: Pautz Carina M , Pinson Catherine L , Jackson Kelli , Burke Marcus A , Kelly Ellen M , Hudson Matthew B
Published: November 2023

Numerous chronic pathological conditions are associated with elevated circulating levels of Angiotensin II (Ang II). A substantial amount of previous research has focused on the effects of elevated Ang II on the heart and vasculature. However, skeletal muscle atrophy occurs during several chronic conditions associated with elevated circulating Ang II, including cardiovascular, renal disease and certain cancers. Thus, more recent research has begun to investigate the potential role of elevated Ang II in the progression of skeletal muscle atrophy. Several microRNAs, including miR‐23a and miR‐182, participate in skeletal muscle atrophy by regulating the level of key atrophy‐inducing proteins. Previously, we demonstrated that the intracellular levels of these microRNAs are reduced in in C2C12 myotubes within 1–2 hours following the administration of glucocorticoids, and this rapid change in key microRNAs may be one of the initial steps in the muscle atrophy process. Therefore, the purpose of the present study was to investigate if Ang II administration to C2C12 myotubes activates muscle atrophy signaling potentially through altered intracellular levels of key microRNAs. Administration of Ang II (1μM) to myotubes resulted in a significant decrease in both miR‐23a (~38%) and miR‐182 (~31%) at 24 hours. However, miR‐23a was significantly decreased (~28%) within half an hour while miR‐182 was not significantly decreased (~42%) until three hrs. Both miR‐23a and miR‐182 returned to baseline levels 48 hours following Ang II administration. Further, 24 hours following Ang II administration MuRF‐1 was significantly increased (~21%) and while Atrogin‐1 was significantly increased at 48 hrs (75These findings demonstrate that Ang II decreases the level of microRNAs known to participate in muscle atrophy, and this decrease occurs prior to the elevation of Atrogin‐1 and MuRF1. This data suggests a possible miRNA‐mediated regulation of Ang II‐induced skeletal muscle atrophy.

Support or Funding Information

Supported by NIH GM087239
Dual Specificity Phosphatase and Pro Isomerase Domain Containing 1 (Dupd1) is Upregulated During Neurogenic Skeletal Muscle Atrophy and is Differentially Expressed in MuRF1‐null Mice
Authors: West Rita , Waddell David
Published: November 2023

Skeletal muscle atrophy is caused by a decrease in muscle size and strength and results from a range of physiological conditions, including denervation, immobilization, corticosteroid exposure and aging. Dual Specificity Phosphatase and Pro Isomerase Domain Containing 1 (Dupd1) has been identified as a novel atrophy‐induced gene in skeletal muscle and has been found to be differentially regulated in wild‐type mice compared to Muscle RING Finger 1 (MuRF1) knockout mice in response to denervation. Muscle RING Finger 1 (MuRF1), an E3 ubiquitin ligase, has previously been shown to be upregulated under almost all conditions of skeletal muscle wasting, is an important marker for skeletal muscle atrophy, and is believed to play an important role in targeting proteins for degradation. However, preliminary data described in this study provides evidence that MuRF1 may also act as a transcriptional modulator of atrophy‐induced gene activity, including the regulation of Dupd1. Microarray data revealed that Dupd1 expression is significantly induced at 3 days and 14 days post‐denervation in wild‐type mice, while Dupd1 expression is dramatically blunted in MuRF1‐null mice at both 3 days and 14 days post‐denervation. The Dupd1 gene codes for a dual specificity phosphatase protein that can dephosphorylate tyrosine and serine/threonine phosphorylated amino acid residues on substrate proteins. Dupd1, thought to be an atypical dual specificity phosphatase (DUSP), is believed to be a mitogen‐activated protein kinase phosphatase (MKP) and is likely capable of dephosphorylating mitogen‐activated protein kinases (MAPK). The results presented here in combination with additional research into the transcriptional regulation and function of Dupd1 in skeletal muscle helps contribute new insight into the molecular genetic mechanisms of muscle atrophy and could provide a more complete understanding of how MuRF1 may transcriptionally regulate neurogenic atrophy‐induced gene expression during muscle wasting.

Support or Funding Information

The work was support by University of North Florida Transformational Learning Opportunity grants to D.W.
Inflammatory Signaling Regulation of Eccentric Contraction–induced Muscle Protein Synthesis in Cachectic Skeletal Muscle
Authors: Hardee Justin P , Gao Song , VanderVeen Brandon N , Fix Dennis K , Carson James A
Published: November 2023

Eccentric muscle contractions (ECC) induce growth that is associated with increased protein synthesis regulated by mTORC1. While disrupted muscle protein turnover occurs during cancer cachexia, cachectic muscle's capacity to respond to ECC is not well understood. Repeated ECC bouts during the progression of cachexia can attenuate muscle mass loss, reduce muscle inflammatory signaling, and decrease AMPK activation. However, cachectic muscle's ability to induce protein synthesis through mTORC1 has not examined. Therefore, we examined if cancer‐induced muscle inflammatory signaling involving STAT3 and NFkB could disrupt ECC‐induced protein synthesis. Either pharmacological (PDTC, a STAT3/NFkB inhibitor) or non‐pharmacological (ECC training) treatments were used to alter muscle inflammatory signaling. mTORC1 signaling and protein synthesis was examined 3h after a single bout of ECC in C57BL/6 (B6; N=9) and cachectic ApcMin/+ (MIN; N=9; 16% BW loss) mice. A subset of MIN mice (N=6; 17% BW loss) also received a single PDTC injection 24h prior to acute muscle contraction. The acute response after ECC training (8 bouts over 2 weeks) in C57BL/6 (N=8) and MIN mice (N=9; 15% BW loss) was also examined. In all experiments the left tibialis anterior (TA) performed ECC while the right TA served as intra‐animal control. Cachexia decreased TA muscle mass, mTORC1 signaling, and protein synthesis when compared to B6 controls. While the ECC induction of p70S6K(T389) phosphorylation was not attenuated by cachexia, the protein synthesis induction by ECC remained suppressed compared to B6 controls. Inhibition of STAT3/NFkB signaling increased basal muscle protein synthesis in MIN mice, which was further enhanced by ECC. The acute ECC induction of muscle protein synthesis was not altered by training. These data demonstrate that basal muscle protein synthesis in cachectic muscle is regulated by muscle inflammatory signaling. However, cachectic muscle inflammatory signaling does not alter the ECC induction of mTORC1 signaling and muscle protein synthesis.

Support or Funding Information

Supported by NCI R01‐CA121249 (JAC) and an ACSM Foundation Research Grant (JPH).
Satellite Cell Depletion Impacts Skeletal Muscle Recovery Following a Burn Injury
Authors: Fry Christopher S , Cambias Lauren A , Prasai Anesh , Wang Ye , El Ayadi Amina , Herndon David , Suman Oscar , Finnerty Celeste
Published: November 2023

Severe burn results in profound skeletal muscle atrophy; persistent muscle atrophy and weakness are major complications that hamper recovery from burn injury. Many factors contribute to the erosion of muscle mass following burn trauma, and we previously showed concurrent activation and apoptosis of muscle satellite cells (SC) following a burn injury in pediatric patients. To determine the necessity of satellite cells during muscle recovery following a burn injury, we utilized a genetically modified mouse model (Pax7‐DTA) that allows for the conditional depletion of satellite cells in skeletal muscle. Additionally, mice were provided 5‐ethynyl‐2′‐deoxyuridine (EdU) to determine satellite cell proliferation, activation and fusion. Juvenile SC‐wild type and SC‐depleted mice (8 weeks of age) were randomized to sham or burn injury, consisting of a dorsal scald burn injury covering 30% of total body surface area. Both hind‐limb and dorsal muscles were studied at 7, 14 and 21 days post‐burn. SC‐depleted mice had >93% fewer SC than SC‐wild type (P<0.05). Burn injury induced robust atrophy in muscles located both proximal and distal to the injury site (~30% decrease in fiber cross‐sectional area, P<0.05). Additionally, burn injury induced skeletal muscle regeneration, satellite cell proliferation and fusion. Depletion of satellite cells impaired post‐burn muscle recovery. These findings support an integral role for satellite cells in the etiology of lean tissue recovery following a severe burn injury.

Support or Funding Information

This project was supported by a pilot grant from the UTMB Department of Surgery and NIH grants P30 AG024832, P50 GM60338, R01 GM56687, R01 HD049471 and Shriners grants SHC 80480 and SHC 80500.
Differential Expression of the Angiotensin II Type 1 Receptor Amongst Various Skeletal Muscle Types
Authors: Hinkley J. Matthew , Morton Aaron B , Smuder Ashley J , Powers Scott K
Published: November 2023

Prolonged periods of skeletal muscle inactivity (e.g. limb immobilization and mechanical ventilation) results in muscle fiber atrophy. However, the rate of disuse muscle atrophy differs between skeletal muscles, as fiber atrophy occurs rapidly in the diaphragm during mechanical ventilation in comparison to limb muscles exposed to prolonged periods of inactivity. The mechanism(s) that explain the differential response between these muscles remains unknown. The angiotensin II type 1 (AT1) receptor, while widely recognized for its role on blood pressure and fluid balance regulation, has recently been implicated as a potential regulator of skeletal muscle mass; however, presence of the receptor in skeletal muscle is controversial. To determine if the diaphragm and limb skeletal muscles exhibit differential expression of the AT1 receptor, samples from the diaphragm and limb muscles (i.e., soleus, extensor digitorum longus, and plantaris) were obtained from female Sprague‐Dawley rats. Presence of the AT1 receptor was assessed by immunoblot analysis and in vitro binding of the fluorescent‐labeled ligand angiotensin II (Ang II). Interestingly, both protein content and in vitro Ang II binding revealed a significantly higher presence of the AT1 receptor in the diaphragm in comparison to all limb skeletal muscles investigated. To further elucidate the potential role of the AT1 receptor in mediating skeletal muscle atrophy, we examined alterations in mRNA expression of the AT1 receptor under disuse conditions of the diaphragm (prolonged mechanical ventilation) and the soleus muscle (limb immobilization). Surprisingly, although both the diaphragm and soleus muscle experienced atrophy, these muscles revealed a differential response in AT1 receptor expression. Specifically, mRNA expression of the AT1 receptor increased (~1.9‐fold) in the diaphragm following mechanical ventilation, whereas limb immobilization resulted in a decrease (~0.6‐fold) in receptor expression in the soleus muscle. Together, these results indicate that skeletal muscle contains a functional AT1 receptor that is differentially regulated between the diaphragm and limb skeletal muscles in control conditions and during prolonged periods of muscle inactivity. These data are consistent with the notion that the AT1 receptor may be a contributing factor in the differential atrophic response of skeletal muscle following prolonged durations of muscle inactivity.

Support or Funding Information

NIH AR064189 and HD043730
Effects of Moderate Iron Loading on Skeletal Muscle Function and Oxidative Injury
Authors: Liang Chen , Benson Marisa , DeRuisseau Keith C
Published: November 2023

Skeletal muscle iron overload is known to increase oxidative injury and impair contractile function. However, the impact of a moderate, physiologically‐relevant degree of muscle iron loading on contractile function has not been investigated. Thus, this study examined effects of moderate iron loading on skeletal muscle function and oxidative injury induced by subcutaneous injections of iron dextran. Young‐adult male mice received injections of iron dextran (4 mg iron/200μL) or vehicle (dextrose) 5 days per week for a period of two weeks (n=10/group). One day following the last injection the soleus muscle was harvested to assess levels of non‐heme iron (NHI), oxidative injury, and contractile properties. Liver and soleus NHI was approximately 4‐fold greater in mice that received injections of iron compared to vehicle (p<0.05). No difference in animal body mass or soleus muscle mass was observed (p>0.05). Maximal specific tension of the soleus was lower among iron loaded animals (22.4±0.1 N/cm2) compared to controls (26.2±0.9 N/cm2; p<0.05). However, soleus lipid peroxidation (4‐hydroxynoneal) and protein oxidation (protein carbonyls) levels were not different between the groups (p>0.05). In summary, a moderate elevation in muscle iron reduced contractile function by a mechanism that does not appear to involve oxidative stress. Additional experiments are being conducted to reveal a possible mechanism behind the iron‐mediated reduction in muscle force production.

Support or Funding Information

Supported by the Syracuse University SOE
Curcumin Supplementation Effects on Aging Skeletal Muscle
Authors: Receno Candace N , Liang Chen , Korol Donna L , DeRuisseau Keith C
Published: November 2023

The decline in muscle mass and function with age, termed sarcopenia, leads to an inability to perform normal daily activities and a subsequent deterioration in quality of life. An increase in oxidative stress that results from an inability to adequately quench reactive oxygen species has been cited as an important mechanism of sarcopenia. Curcumin, the active ingredient in the spice turmeric, has garnered much attention due to its antioxidative properties. Although curcumin's antioxidant properties may also make it beneficial to sarcopenia, this theory has not been tested. Thus, this study examined the effects of curcumin supplementation on muscle force characteristics in aging rats. Fourteen thirty‐two‐month‐old, male F344xBN rats were provided purified diets (AIN‐93M) for four months. One group received the diet ad libitum (CON, n=5), a second group consumed the same diet which also contained 0.2% curcumin (CUR, n=4), and a third, pair fed (PAIR, n=4) group was included that received the purified diet in an amount equal to the food consumed by CUR animals. Following the supplementation period, the plantaris was assessed for in vivo twitch and tetanic force generation measurements. Body mass, muscle mass, and contractile characteristics were analyzed using independent sample t‐tests. Data are expressed as mean±SEM. CUR and PAIR animals had a lower dietary intake compared to the CON group, however, animal body mass did not differ between groups (p>0.05). Muscle mass (g) was significantly lower in the PAIR group (0.190±.019, p<0.05), while CUR and CON muscle mass was similar (0.285±0.016 and 0.306±0.014, respectively). Peak twitch and peak tetanic tension were not significantly different between groups (p>.05). However, normalized peak tetanic tension (N/g) was 30% higher in the CUR group compared to the PAIR group (CUR=77.52±9.881, PAIR=59.6±2.556). Studies are on‐going to increase sample size numbers and continue testing the effects of curcumin on muscle function parameters. Preliminary findings suggest that dietary curcumin may attenuate the declines in muscle mass incurred by a reduced food intake among pair fed, aging rats. We are also investigating the mechanisms by which curcumin may elicit these changes, which include measurements of antioxidant expression and activity, and oxidative stress.

Support or Funding Information

Supported by the NIH, National Institute on Aging, Grant #1R36AG050734 ‐ 01 (CNR).
Screening of compounds regulating FOXO1 transcriptional activity
Authors: Onishi Takumi , Hirose Yuma , Hatazawa Yukino , Kamei Yasutomi
Published: November 2023

Skeletal muscle is the largest organ in the human body, and plays a critical role in energy expenditure, glucose metabolism, and exercise. The mass and composition of skeletal muscle affect its function, and changed by physical activity, the environment, and disease. For example, malnutrition and inactivity, such as aging, bed rest, and plaster casts, cause muscle atrophy. FOXO1, a member of the forkhead‐type transcriptional factors, is up‐regulated during muscle atrophy. FOXO1 enhances expression of genes involved in protein degradation by the ubiquitin‐proteasome system and autophagy. In fact, we have shown that transgenic mice specifically overexpressing FOXO1 in skeletal muscles exhibited muscle atrophy. Also, deletion of FOXO1 inhibited expression of enzymes involved in protein degradation induced during muscle atrophy. Namely, FOXO1 is a key regulator of muscle atrophy. Thus, we attempt to search for compounds that inhibit FOXO1 transcriptional activity. We establish a system to evaluate FOXO1 transcriptional activity by using FOXO1 conjugated with the GAL4‐DNA binding domain. Indeed, luciferase reporter expression was induced by FOXO1. Using this reporter system, we screened compounds in terms of their ability to inhibit the FOXO1 pathway. In this study, we found several compounds attenuated luciferase activity in 400 biologically active substances from natural products and plants. These compounds likely inhibit FOXO1 transcriptional activity and may attenuate muscle atrophy.
TRB3 Regulates Protein Turnover in Mouse Skeletal Muscle
Authors: Choi Ran Hee , McConahay Abigail , Hardee Justin P , Carson James A , Hirshman Michael F , Goodyear Laurie J , Koh Ho‐Jin
Published: November 2023

Skeletal muscle atrophy is a critical condition associated with several diseases, including cancer cachexia, diabetes, and cardiac failure. Skeletal muscle mass loss is related to disrupted protein turnover involving increased protein degradation and suppressed protein synthesis. The IGF1/PI3K/Akt pathway has emerged as a major signaling cascade of protein turnover through mTOR (protein synthesis) and FOXOs (protein degradation) signaling, and is activated by anabolic signals such as insulin. Recently, TRB3, a mammalian homologue of Drosophila Tribbles 3, has been found in multiple tissues, including liver, fat, pancreas, and skeletal muscle, and negatively regulates Akt via direct binding to its phosphorylation sites (S473 and T308). Although increased TRB3 expression has been associated with insulin resistance in in vitro and in vivo models, its role in the regulation of skeletal muscle mass is not known. Here, we tested the hypothesis that TRB3 negatively regulates skeletal muscle mass in denervation‐induced atrophy. We performed denervation of the sciatic nerve in one leg while the contralateral leg served as a control. At 9 days post‐denervation, there was a robust increased in TRB3 mRNA (12.2‐fold) and protein expression (16.2‐fold) compared to the control. In addition, skeletal muscle weight was reduced by 20–30% after 9 days of denervation, and insulin‐stimulated IRS1 Y612 (23%, P<0.01) and Akt T308 (22%, P<0.001) phosphorylation was attenuated. Muscle‐specific transgenic mice overexpressing TRB3 (TRB3TG) exhibited reduced skeletal muscle mass compared to wild type (TA; 10%, P=0.056, Gas; 20%, P=0.079), with substantially elevated mRNA expression of skeletal muscle specific‐ubiquitin ligases, Atrogin‐1 (WT:1.00±0.33, TG: 1.6±0.16, A.U.; P=0.073) and MURF‐1 (WT: 1.00±0.1, TG: 1.7±0.2, A.U.; P<0.01). We then examined if skeletal muscle TRB3 overexpression would affect protein synthesis measured by assessing the incorporation of puromycin into nascent peptide chains. Muscle protein synthesis in TRB3TG mice was reduced by 60%. Grip strength was also decreased by 15% in TRB3TG mice when compared to wild type. However, muscle‐specific TRB3 overexpression did not accelerate or inhibit denervation‐induced atrophy. In contrast, whole body TRB3 knockout mice (TRB3KO) displayed a 90% decrease in Atrogin‐1 protein expression compared to wild type (WT:1.00±0.03, KO: 0.1±0.01, A.U.; P<0.001). Furthermore, TRB3KO mice that received denervation for 9 days tended to prevent increasing of Atrogin‐1 (WT: 2.27±0.6; KO:1.39±0.07, A.U.; P=0.33) and MURF‐1 (WT: 2.6±0.5; KO: 1.72±0.23, A.U; P=0.093) protein expression compared to wild type. These data suggest that TRB3 could be a critical regulator of skeletal muscle mass under atrophic conditions and could be a target for therapeutic treatment.