The Regulation of Skeletal Muscle Protein Turnover During the Progression of Cancer Cachexia in the \u3cem\u3eApc\u3csup\u3eMin/+\u3c/sup\u3e\u3c/em\u3e Mouse

Muscle wasting that occurs with cancer cachexia is caused by an imbalance in the rates of muscle protein synthesis and degradation. The Apc(Min/+) mouse is a model of colorectal cancer that develops cachexia that is dependent on circulating IL-6. However, the IL-6 regulation of muscle protein turnover during the initiation and progression of cachexia in the Apc(Min/+) mouse is not known. Cachexia progression was studied in Apc(Min/+) mice that were either weight stable (WS) or had initial (≤5%), intermediate (6-19%), or extreme (≥20%) body weight loss. The initiation of cachexia reduced %MPS 19% and a further ∼50% with additional weight loss. Muscle IGF-1 mRNA expression and mTOR targets were suppressed with the progression of body weight loss, while muscle AMPK phosphorylation (Thr 172), AMPK activity, and raptor phosphorylation (Ser 792) were not increased with the initiation of weight loss, but were induced as cachexia progressed. ATP dependent protein degradation increased during the initiation and progression of cachexia. However, ATP independent protein degradation was not increased until cachexia had progressed beyond the initial phase. IL-6 receptor antibody administration prevented body weight loss and suppressed muscle protein degradation, without any effect on muscle %MPS or IGF-1 associated signaling. In summary, the %MPS reduction during the initiation of cachexia is associated with IGF-1/mTOR signaling repression, while muscle AMPK activation and activation of ATP independent protein degradation occur later in the progression of cachexia. IL-6 receptor antibody treatment blocked cachexia progression through the suppression of muscle protein degradation, while not rescuing the suppression of muscle protein synthesis. Attenuation of IL-6 signaling was effective in blocking the progression of cachexia, but not sufficient to reverse the process

IL-6 Regulation on Skeletal Muscle Mitochondrial Remodeling During Cancer Cachexia in the \u3cem\u3eApc\u3csup\u3eMin/+\u3c/sup\u3e\u3c/em\u3e Mouse

BACKGROUND: Muscle protein turnover regulation during cancer cachexia is being rapidly defined, and skeletal muscle mitochondria function appears coupled to processes regulating muscle wasting. Skeletal muscle oxidative capacity and the expression of proteins regulating mitochondrial biogenesis and dynamics are disrupted in severely cachectic ApcMin/+ mice. It has not been determined if these changes occur at the onset of cachexia and are necessary for the progression of muscle wasting. Exercise and anti-cytokine therapies have proven effective in preventing cachexia development in tumor bearing mice, while their effect on mitochondrial content, biogenesis and dynamics is not well understood. The purposes of this study were to 1) determine IL-6 regulation on mitochondrial remodeling/dysfunction during the progression of cancer cachexia and 2) to determine if exercise training can attenuate mitochondrial dysfunction and the induction of proteolytic pathways during IL-6 induced cancer cachexia. METHODS: ApcMin/+ mice were examined during the progression of cachexia, after systemic interleukin (IL)-6r antibody treatment, or after IL-6 over-expression with or without exercise. Direct effects of IL-6 on mitochondrial remodeling were examined in cultured C2C12 myoblasts. RESULTS: Mitochondrial content was not reduced during the initial development of cachexia, while muscle PGC-1α and fusion (Mfn1, Mfn2) protein expression was repressed. With progressive weight loss mitochondrial content decreased, PGC-1α and fusion proteins were further suppressed, and fission protein (FIS1) was induced. IL-6 receptor antibody administration after the onset of cachexia improved mitochondrial content, PGC-1α, Mfn1/Mfn2 and FIS1 protein expression. IL-6 over-expression in pre-cachectic mice accelerated body weight loss and muscle wasting, without reducing mitochondrial content, while PGC-1α and Mfn1/Mfn2 protein expression was suppressed and FIS1 protein expression induced. Exercise normalized these IL-6 induced effects. C2C12 myotubes administered IL-6 had increased FIS1 protein expression, increased oxidative stress, and reduced PGC-1α gene expression without altered mitochondrial protein expression. CONCLUSIONS: Altered expression of proteins regulating mitochondrial biogenesis and fusion are early events in the initiation of cachexia regulated by IL-6, which precede the loss of muscle mitochondrial content. Furthermore, IL-6 induced mitochondrial remodeling and proteolysis can be rescued with moderate exercise training even in the presence of high circulating IL-6 levels

The Regulation of Skeletal Muscle Protein Turnover during the Progression of Cancer Cachexia in the ApcMin/+ Mouse

Muscle wasting that occurs with cancer cachexia is caused by an imbalance in the rates of muscle protein synthesis and degradation. The ApcMin/+ mouse is a model of colorectal cancer that develops cachexia that is dependent on circulating IL-6. However, the IL-6 regulation of muscle protein turnover during the initiation and progression of cachexia in the ApcMin/+ mouse is not known. Cachexia progression was studied in ApcMin/+ mice that were either weight stable (WS) or had initial (≤5%), intermediate (6–19%), or extreme (≥20%) body weight loss. The initiation of cachexia reduced %MPS 19% and a further ∼50% with additional weight loss. Muscle IGF-1 mRNA expression and mTOR targets were suppressed with the progression of body weight loss, while muscle AMPK phosphorylation (Thr 172), AMPK activity, and raptor phosphorylation (Ser 792) were not increased with the initiation of weight loss, but were induced as cachexia progressed. ATP dependent protein degradation increased during the initiation and progression of cachexia. However, ATP independent protein degradation was not increased until cachexia had progressed beyond the initial phase. IL-6 receptor antibody administration prevented body weight loss and suppressed muscle protein degradation, without any effect on muscle %MPS or IGF-1 associated signaling. In summary, the %MPS reduction during the initiation of cachexia is associated with IGF-1/mTOR signaling repression, while muscle AMPK activation and activation of ATP independent protein degradation occur later in the progression of cachexia. IL-6 receptor antibody treatment blocked cachexia progression through the suppression of muscle protein degradation, while not rescuing the suppression of muscle protein synthesis. Attenuation of IL-6 signaling was effective in blocking the progression of cachexia, but not sufficient to reverse the process

Glucocorticoid Receptor (NR3C1) Variants Associate with the Muscle Strength and Size Response to Resistance Training

Glucocorticoid receptor (NR3C1) polymorphisms associate with obesity, muscle strength, and cortisol sensitivity. We examined associations among four NR3C1 polymorphisms and the muscle response to resistance training (RT). European-American adults (n = 602, 23.8±0.4yr) completed a 12 week unilateral arm RT program. Maximum voluntary contraction (MVC) assessed isometric strength (kg) and MRI assessed biceps size (cm2) pre- and post-resistance training. Subjects were genotyped for NR3C1 -2722G>A, -1887G>A, -1017T>C, and +363A>G. Men carrying the -2722G allele gained less relative MVC (17.3±1.2vs33.5±6.1%) (p = 0.010) than AA homozygotes; men with -1887GG gained greater relative MVC than A allele carriers (19.6±1.4vs13.2±2.3%) (p = 0.016). Women carrying the -1017T allele gained greater relative size (18.7±0.5vs16.1±0.9%) (p = 0.016) than CC homozygotes. We found sex-specific NR3C1 associations with the muscle strength and size response to RT. Future studies should investigate whether these associations are partially explained by cortisol’s actions in muscle tissue as they interact with sex differences in cortisol production.https://doi.org/10.1371/journal.pone.014811

Subcutaneous Fat Alterations Resulting From An Upper-Body Resistance Training Program

PURPOSE: It is believed spot reduction, the exercise-induced localized loss of subcutaneous fat, does not occur as a result of an exercise program; however, evidence as a whole has been inconsistent. To reexamine this concept, we compared subcutaneous fat measurements before and after resistance training among 104 subjects (45 men, 59 women). METHODS: Subjects participated in 12 wk of supervised resistance training of their nondominant arm. Magnetic resonance imaging and skinfold calipers examined subcutaneous fat in the nondominant (trained) and dominant (untrained) arms before and after resistance training. Repeated-measures ANCOVA tested for subcutaneous fat differences within and between arms before, after, and from before to after resistance training by gender and measurement technique, with BMI and age as covariates. Simple linear regression compared subcutaneous fat changes before and after resistance training as assessed by MRI and skinfold. RESULTS: Subcutaneous fat, measured by skinfold, decreased in the trained arm and not the untrained arm in the men (P \u3c 0.01); it was similar in the total sample and in the women (P \u3e 0.05). MRI determinations of subcutaneous fat changes were not different between arms in the total sample and by gender (P \u3e 0.05). CONCLUSION: Subcutaneous fat changes resulting from resistance training varied by gender and assessment technique. Skinfold findings indicate that spot reduction occurred in men but not in women. In contrast, MRI found a generalized subcutaneous fat loss independent of gender, supporting the notion that spot reduction does not occur as a result of resistance training. MRI, sensitive to changes along the entire upper arm, detected greater variation in resistance training responses, preventing significant differences between trained and untrained arms. Variation in upper-arm resistance training response was not evident from a single skinfold measurement at the belly of the muscle. ©2007The American College of Sports Medicine

Myostatin And Follistatin Polymorphisms Interact With Muscle Phenotypes And Ethnicity

Purpose: We examined associations among myostatin (MSTN) 2379 A \u3e G and 163 G \u3e A and follistatin (FST) -5003 A \u3e T and -833 G \u3e T single nucleotide polymorphisms (SNP) on the muscle size and the strength response to resistance training (RT). Methods: Subjects (n = 645, age = 24.1 ± 0.2 yr, body mass index [BMI] = 24.2 ± 0.2 kg m -2) self-disclosed themselves as Caucasian (78.9%), African American (3.6%), Asian (8.4%), Hispanic (5.0%), or Other (4.2%). They were genotyped for MSTN 2379 A \u3e G (n = 645), MSTN 163 G \u3e A (n = 639), FST -5003 A \u3e T (n = 580), and FST -833 G \u3e T (n = 603). We assessed dynamic (one repetition maximum [1RM]) and isometric (maximum voluntary contraction [MVC]) muscle strength and size (cross-sectional area [CSA]) of the elbow flexors before and after 12 wk of unilateral upper-arm RT. Repeated-measures ANCOVA tested associations among genetic variants and muscle phenotypes with age and BMI as covariates. Results: Baseline MVC was greater among African Americans who were carriers of the MSTN G 2379 allele (AG/GG, n = 15) than the A2379A homozygotes (n = 8; 64.2 ± 6.8 vs 49.8 ± 8.7 kg). African Americans who were carriers of the FST T -5003 allele (n = 12) had greater baseline 1RM (11.9 ± 0.7 vs 8.8 ± 0.5 kg) and CSA (24.4 ± 1.3 vs 19.1 ± 1.2 cm 2) than African Americans with the A-5003A genotype (n = 14; P \u3c 0.05). No MSTN or FST genotype and muscle phenotype associations were found among the other ethnic groups (P \u3e 0.05). Conclusion: MSTN 2379 A \u3e G and FST -5003 A \u3e T were associated with baseline muscle strength and size among African Americans only. These ethnic-specific associations are hypothesis generating and should be confirmed in a larger sample of African Americans. Copyright © 2009 by The American College of Sports Medicine

Ace Id Genotype And The Muscle Strength And Size Response To Unilateral Resistance Training

Purpose: To examine associations among the angiotensin I-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism and the response to a 12-wk (2 d·wk-1) unilateral, upper-arm resistance training (RT) program in the trained (T, nondominant) and untrained (UT, dominant) arms. Methods: Subjects were 631 (mean ± SEM, 24.2 ± 0.2 yr) white (80%) men (42%) and women (58%). The ACE ID genotype was in Hardy-Weinberg equilibrium with frequencies of 23.1, 46.1, and 30.8% for ACE II, ID, and DD, respectively (x2 = 1.688, P = 0.430). Maximum voluntary contraction (MVC) and one-repetition maximum (1RM) assessed peak elbow flexor muscle strength. Magnetic resonance imaging measured biceps muscle cross-sectional area (CSA). Multiple variable and repeated-measures ANCOVA tested whether muscle strength and size differed at baseline and pre- to post-RT among T and UT and ACE ID genotype. Results: Baseline muscle strength and size were greater in UT than T (P \u3c 0.001) and did not differ among ACE ID genotype in either arm (P ≥ 0.05). In T, MVC increases were greater for ACE II/ID (22%) than DD (17%) (P \u3c 0.05), whereas IRM (51%) and CSA (19%) gains were not different among ACE ID genotype pre- to post-RT (P ≥ 0.05). In UT, MVC increased among ACE II/ID (7%) (P \u3c 0.001) but was similar among ACE DD (2%) pre- to post-RT (P ≥ 0.05). In UT, IRM (11%) and CSA (2%) increases were greater for ACE DD/ID than ACE II (1RM, 7%; CSA, -0.1%) (P \u3c 0.05). ACE ID genotype explained approximately 1% of the MVC response to RT in T and approximately 2% of MVC, 2% of IRM, and 4% of CSA response in UT (P \u3c 0.05). Conclusion: ACE ID genotype is associated with the contralateral effects of unilateral RT, perhaps more so than with the muscle strength and size adaptations that result from RT. Copyright © 2006 by the American College of Sports Medicine

Exercise-induced hypoalgesia: A meta-analysis of exercise dosing for the treatment of chronic pain

OBJECTIVE: Increasing evidence purports exercise as a first-line therapeutic for the treatment of nearly all forms of chronic pain. However, knowledge of efficacious dosing respective to treatment modality and pain condition is virtually absent in the literature. The purpose of this analysis was to calculate the extent to which exercise treatment shows dose-dependent effects similar to what is seen with pharmacological treatments. METHODS: A recently published comprehensive review of exercise and physical activity for chronic pain in adults was identified in May 2017. This report reviewed different physical activity and exercise interventions and their effectiveness in reducing pain severity and found overall modest effects of exercise in the treatment of pain. We analyzed this existing data set, focusing specifically on the dose of exercise intervention in these studies. We re-analyzed data from 75 studies looking at benefits of time of exercising per week, frequency of exercise per week, duration of intervention (in weeks), and estimated intensity of exercise. RESULTS: Analysis revealed a significant positive correlation with exercise duration and analgesic effect on neck pain. Multiple linear regression modeling of these data predicted that increasing the frequency of exercise sessions per week is most likely to have a positive effect on chronic pain patients. DISCUSSION: Modest effects were observed with one significant correlation between duration and pain effect for neck pain. Overall, these results provide insufficient evidence to conclude the presence of a strong dose effect of exercise in pain, but our modeling data provide tes predictions that can be used to design future studies to explicitly test the question of dose in specific patient populations

High-Frequency Stimulation on Skeletal Muscle Maintenance in Female Cachectic Mice

Cancer cachexia, an unintentional body weight loss due to cancer, affects patients\u27 survival, quality of life, and response to chemotherapy. Although exercise training is a promising intervention to prevent and treat cancer cachexia, our mechanistic understanding of cachexia\u27s effect on contraction-induced muscle adaptation has been limited to the examination of male mice. Because sex can affect muscle regeneration and response to contraction in humans and mice, the effect of cachexia on the female response to eccentric contraction warrants further investigation. Purpose The purpose of this study was to determine whether high-frequency electric stimulation (HFES) could attenuate muscle mass loss during the progression of cancer cachexia in female tumor-bearing mice. Methods Female wild-type (WT) and ApcMin/+ (Min) mice (16-18 wk old) performed either repeated bouts or a single bout of HFES (10 sets of 6 repetitions, 22 min), which eccentrically contracts the tibialis anterior (TA) muscle. TA myofiber size, oxidative capacity, anabolic signaling, and catabolic signaling were examined. Results Min had reduced TA muscle mass and type IIa and type IIb fiber sizes compared with WT. HFES increased the muscle weight and the mean cross-sectional area of type IIa and type IIb fibers in WT and Min mice. HFES increased mTOR signaling and myofibrillar protein synthesis and attenuated cachexia-induced AMPK activity. HFES attenuated the cachexia-associated decrease in skeletal muscle oxidative capacity. Conclusion HFES in female mice can activate muscle protein synthesis through mTOR signaling and repeated bouts of contraction can attenuate cancer-induced muscle mass loss

The dosing of aerobic exercise therapy on experimentally-induced pain in healthy female participants

ABSTRACT Knowledge of efficacious dosing respective to exercise type and pain condition is extremely limited in the literature. This study aimed to determine the impact of dose of moderate intensity treadmill walking on experimentally-induced pain in healthy human participants. Forty females were divided into 4 groups: control (no exercise), low dose exercise (3x/wk), moderate dose exercise (5x/wk) or high dose exercise (10x/wk). Over a 7-day period, subjects performed treadmill walking during assigned exercise days. Both qualitative and quantitative measures of pain were measured at baseline, during the trial, and 24 hrs post-final intervention session via sensitivity thresholds to painful thermal and painful pressure stimulation. Significant effects of treatment were found post intervention for constant pressure pain intensity (p=0.0016) and pain unpleasantness ratings (p=0.0014). Post-hoc tests revealed significant differences between control and moderate and control and high dose groups for constant pressure pain intensity (p=0.0015), (p=0.0094), respectively and constant pressure pain unpleasantness(p=0.0040), (p=0.0040), respectively. Moderate and high dose groups had the greatest reductions in ratings of pain, suggesting that our lowest dose of exercise was not sufficient to reduce pain and that the moderate dose of exercise may be a sufficient starting dose for exercise-based adjuvant pain therapy