scholarly journals Eccentric contraction-induced myofiber growth in tumor-bearing mice

2016 ◽  
Vol 120 (1) ◽  
pp. 29-37 ◽  
Author(s):  
Justin P. Hardee ◽  
Joshua E. Mangum ◽  
Song Gao ◽  
Shuichi Sato ◽  
Kimbell L. Hetzler ◽  
...  

Cancer cachexia is characterized by the progressive loss of skeletal muscle mass. While mouse skeletal muscle's response to an acute bout of stimulated low-frequency concentric muscle contractions is disrupted by cachexia, gaps remain in our understanding of cachexia's effects on eccentric contraction-induced muscle growth. The purpose of this study was to determine whether repeated bouts of stimulated high-frequency eccentric muscle contractions [high-frequency electrical muscle stimulation (HFES)] could stimulate myofiber growth during cancer cachexia progression, and whether this training disrupted muscle signaling associated with wasting. Male Apc Min/+ mice initiating cachexia ( N = 9) performed seven bouts of HFES-induced eccentric contractions of the left tibialis anterior muscle over 2 wk. The right tibialis anterior served as the control, and mice were killed 48 h after the last stimulation. Age-matched C57BL/6 mice ( N = 9) served as wild-type controls. Apc Min/+ mice lost body weight, muscle mass, and type IIA, IIX, and IIB myofiber cross-sectional area. HFES increased myofiber cross-sectional area of all fiber types, regardless of cachexia. Cachexia increased muscle noncontractile tissue, which was attenuated by HFES. Cachexia decreased the percentage of high succinate dehydrogenase activity myofibers, which was increased by HFES, regardless of cachexia. While cachexia activated AMP kinase, STAT3, and ERK1/2 signaling, HFES decreased AMP kinase phosphorylation, independent of the suppression of STAT3. These results demonstrate that cachectic skeletal muscle can initiate a growth response to repeated eccentric muscle contractions, despite the presence of a systemic cachectic environment.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 222-222 ◽  
Author(s):  
Samuel Craig Brondfield ◽  
Vivian K. Weinberg ◽  
Kathryn M. Koepfgen ◽  
Arturo Molina ◽  
Charles J. Ryan ◽  
...  

222 Background: AA, an inhibitor of androgen biosynthesis, has been shown to prolong overall survival in patients with mCRPC who have previously been treated with chemotherapy. Androgen deprivation therapy (ADT) has been shown to result in muscle wasting in prostate cancer pts. The effects of AA on progression of muscle and fat wasting have not been characterized. We evaluated whether 6 months of AA therapy altered total skeletal muscle mass or adipose mass. Methods: 10 sequential pts who responded to AA therapy for at least 6 months and had available computed tomography (CT) scans were retrospectively selected from the phase I-II COU-AA-002 study. CT image analysis was used to quantify change from baseline in total skeletal muscle and adipose tissue after 6 months of AA treatment. Skeletal muscle and adipose tissue cross-sectional area were calculated at the L3 level using Slice-O-Matic software V4.3. Previously published regression models were used to estimate fat-free mass, fat mass and skeletal muscle mass. Paired t-tests were performed to determine the change in measurements. Results: At baseline, 7 of 10 pts were overweight or obese (body mass index [BMI] > 25 kg/m2), and none were underweight. Advanced muscle wasting (sarcopenia, previously defined as the ratio of skeletal muscle cross-sectional area at L3 level to height < 52.4 cm2/m2) was present at baseline and 6 months in 9 of 10 pts. Over 6 months of AA treatment, pts lost an average of 1.9 kg ± 1.9 kg (p = 0.13). Mean changes (kg) (±standard deviation) in total skeletal muscle mass (−0.80 ± 1.71, p = 0.18) and total non-adipose mass (−1.44 ± 3.09, p = 0.17) were not significant. A significant decrease in total adipose mass (−0.61 ± 0.84, p = 0.048) was observed. Conclusions: Sarcopenia is prevalent in pts with mCRPC. AA was not related to significantly worsening sarcopenia or overall weight loss during the first 6 months of treatment; however, this may reflect a relatively short duration of therapy and/or small sample size. A significant loss of adipose tissue was observed, which is unexpected given the known effects of ADT, which increases adipose mass. Evaluation of additional AA treated patients is ongoing.


2021 ◽  
Author(s):  
Yumin Wang ◽  
Satoshi Ikeda ◽  
Katsunori Ikoma

Abstract Mechanical stimulation has benefits for muscle mass and function. Passive stretching is widely performed in clinical rehabilitation medicine. However, the hypertrophic effects of passive repetitive stretching on senescent skeletal muscles against muscle atrophy remain unknown. We used senescence-accelerated model SAM-P8 mice. The gastrocnemius muscle was passively repetitive stretched by manual ankle dorsiflexion for 15 min, 5 days a week for 2 weeks under deep anesthesia. We examined the effects of passive stretching on muscle mass, myofiber cross-sectional area, muscle fiber type and composition, satellite cell content, mRNA expression of the signaling pathways involved in muscle protein synthesis, muscle-specific ubiquitin ligases, and myogenic regulatory factors. The gastrocnemius muscle weight of the stretched side increased compared with that of the unstretched side. In addition to the increase in muscle mass, muscle fiber cross-sectional area of the stretched side was greater than that of the unstretched side. Passive repetitive stretching significantly increased the mRNA expression level of Akt, p70S6K, 4E-BP1, Myf5, myogenin, MuRF1. Passive repetitive stretching promoted skeletal muscle mass and myofiber cross-sectional area in SAM-P8 mice. These hypertrophic observations are attributable to the stretch-activated signaling pathways involved in protein turnover. These findings are applicable to clinical muscle strengthening and sarcopenia prevention.


2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15137-e15137
Author(s):  
Samuel Craig Brondfield ◽  
Vivian K. Weinberg ◽  
Kathryn M. Koepfgen ◽  
Arturo Molina ◽  
Charles J. Ryan ◽  
...  

e15137 Background: AA, an inhibitor of androgen biosynthesis, has been shown to prolong overall survival in patients with mCRPC who have previously been treated with chemotherapy. ADT has been shown to result in muscle wasting in prostate cancer patients. The effects of AA on progression of muscle and fat wasting have not been characterized. We evaluated whether 6 months of AA therapy altered total skeletal muscle mass or adipose mass. Methods: 10 sequential patients who responded to AA therapy for at least 6 months and had available computed tomography (CT) scans were retrospectively selected from the phase I-II COU-AA-002 study. CT image analysis was used to quantify change from baseline in total skeletal muscle and adipose tissue after 6 months of AA treatment. Skeletal muscle and adipose tissue cross-sectional area were calculated at the L3 level using Slice-O-Matic software V4.3. Previously published regression models were used to estimate fat-free mass, fat mass and skeletal muscle mass. Paired t-tests were performed to determine the change in measurements. Results: At baseline, 7 of 10 patients were overweight or obese (body mass index [BMI] > 25 kg/m2), and none were underweight. Advanced muscle wasting (sarcopenia, previously defined as the ratio of skeletal muscle cross-sectional area at L3 level to height < 52.4 cm2/m2) was present at baseline and 6 months in 9 of 10 pts. Over 6 months of AA treatment, patients lost an average of 1.9 kg ± 3.6 kg (p = 0.13). Mean changes (kg) (±standard deviation) in total skeletal muscle mass (-0.80 ± 1.71, p = 0.18) and total non-adipose mass (-1.44 ± 3.09, p = 0.17) were not significant. A significant decrease in total adipose mass (-0.61 ± 0.84, p = 0.048) was observed. Conclusions: Sarcopenia is prevalent in patients with mCRPC. AA was not related to significantly worsening sarcopenia or overall weight loss during the first 6 months of treatment; however, this may reflect a relatively short duration of therapy and/or small sample size. A significant loss of adipose tissue was observed, which is unexpected given the known effects of ADT, which increases adipose mass. Evaluation of additional AA treated patients is ongoing.


2020 ◽  
Author(s):  
Arik Davidyan ◽  
Keith Baar ◽  
Sue C. Bodine

AbstractTestosterone is considered a potent anabolic agent in skeletal muscle with a well-established role in adolescent growth and development in males. However, alterations in the role of testosterone in the regulation of skeletal muscle mass and function throughout the lifespan has yet to be established. While some studies suggest that testosterone is important for the maintenance of skeletal muscle mass, an understanding of the role this hormone plays in young, adult, and old males with normal and low serum testosterone levels is lacking. We investigated the role testosterone plays in the maintenance of muscle mass by examining the effect of orchiectomy-induced testosterone depletion in C57Bl6 male mice at ages ranging from early postnatal through old age; the age groups we used included 1.5-, 5-, 12-, and 24-month old mice. Following 28 days of testosterone depletion, we assessed mass and fiber cross-sectional-area (CSA) of the tibialis anterior, gastrocnemius, and quadriceps muscles. In addition, we measured global rates of protein synthesis and degradation using the SuNSET method, western blots, and enzyme activity assays. 28 days of testosterone depletion resulted in smaller muscle mass in the two youngest cohorts but had no effect in the two older ones. Mean CSA decreased only in the youngest cohort and only in the tibialis anterior muscle. Testosterone depletion resulted in a general increase in proteasome activity at all ages. We did not detect changes in protein synthesis at the terminal time point. This data suggest that within physiological serum concentrations, testosterone is not important for the maintenance of muscle mass in mature male mice; however, in young mice testosterone is crucial for normal growth.


PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0240278
Author(s):  
Arik Davidyan ◽  
Suraj Pathak ◽  
Keith Baar ◽  
Sue C. Bodine

Testosterone is considered a potent anabolic agent in skeletal muscle with a well-established role in adolescent growth and development in males. However, the role of testosterone in the regulation of skeletal muscle mass and function throughout the lifespan has yet to be fully established. While some studies suggest that testosterone is important for the maintenance of skeletal muscle mass, an understanding of the role this hormone plays in young, adult, and old males with normal and low serum testosterone levels is lacking. We investigated the role testosterone plays in the maintenance of muscle mass by examining the effect of orchiectomy-induced testosterone depletion in C57Bl6 male mice at ages ranging from early postnatal through old age (1.5-, 5-, 12-, and 24-month old mice). Following 28 days of testosterone depletion, we assessed mass and fiber cross-sectional-area (CSA) of the tibialis anterior, gastrocnemius, and quadriceps muscles. In addition, we measured global rates of protein synthesis and degradation using the SuNSET method, western blots, and enzyme activity assays. Twenty-eight days of testosterone depletion resulted in reduced muscle mass in the two youngest cohorts, but had no effect in the two oldest cohorts. Mean CSA decreased only in the youngest cohort and only in the tibialis anterior muscle. Testosterone depletion resulted in a general increase in proteasome activity at all ages. No change in protein synthesis was detected at the terminal time point. These data suggest that within physiological serum concentrations, testosterone may not be critical for the maintenance of muscle mass in mature male mice; however, in young mice testosterone is crucial for normal growth.


2021 ◽  
Vol 11 ◽  
Author(s):  
Tine Vrist Dam ◽  
Line Barner Dalgaard ◽  
Steffen Ringgaard ◽  
Frank Ted Johansen ◽  
Mads Bisgaard Bengtsen ◽  
...  

ContextWomen show an accelerated loss of muscle mass around menopause, possibly related to the decline in estrogen. Furthermore, the anabolic response to resistance exercise seems to be hampered in postmenopausal women.ObjectiveWe aimed to test the hypothesis that transdermal estrogen therapy (ET) amplifies the skeletal muscle response to resistance training in early postmenopausal women.DesignA double-blinded randomized controlled study.SettingDepartment of Public Health, Aarhus University, Denmark.ParticipantsThirty-one healthy, untrained postmenopausal women no more than 5 years past menopause.Intervention(s)Supervised resistance training with placebo (PLC, n = 16) or transdermal ET (n = 15) for 12 weeks.Main Outcome Measure(s)The primary outcome parameter was a cross-sectional area of quadriceps femoris measured by magnetic resonance imaging, and secondary parameters were fat-free mass (dual-energy X-ray absorptiometry), muscle strength, and functional tests.ResultsThe increase in muscle cross-sectional area was significantly greater in the ET group (7.9%) compared with the PLC group (3.9%) (p &lt; 0.05). Similarly, the increase in whole-body fat-free mass was greater in the ET group (5.5%) than in the PLC group (2.9%) (p &lt; 0.05). Handgrip strength increased in ET (p &lt; 0.05) but did not change in the PLC group. Muscle strength parameters, jumping height, and finger strength were all improved after the training period with no difference between groups.ConclusionThe use of transdermal ET enhanced the increase in muscle mass in response to 12 weeks of progressive resistance training in early postmenopausal women.


2003 ◽  
Vol 94 (3) ◽  
pp. 876-882 ◽  
Author(s):  
Thomas J. McLoughlin ◽  
Eleni Mylona ◽  
Troy A. Hornberger ◽  
Karyn A. Esser ◽  
Francis X. Pizza

We determined the effect of muscle contractions resulting from high-frequency electrical stimulation (HFES) on inflammatory cells in rat tibialis anterior (TA), plantaris (Pln), and soleus (Sol) muscles at 6, 24, and 72 h post-HFES. A minimum of four and a maximum of seven rats were analyzed at each time point. HFES, applied to the sciatic nerve, caused the Sol and Pln to contract concentrically and the TA to contract eccentrically. Neutrophils were higher ( P < 0.05) at 6 and 24 h after HFES in the Sol, Pln, and TA muscles relative to control muscles. ED1+ macrophages in the Pln were elevated at 6 and 24 h after HFES and were also elevated in the Sol and TA after HFES relative to controls. ED2+ macrophages in the Sol and TA were elevated at 24 and 72 h after HFES, respectively, and were also elevated in the Pln after HFES relative to controls. In contrast to the TA muscles, the Pln and Sol muscles showed no gross histological abnormalities. Collectively, these data indicate that both eccentric and concentric contractions can increase inflammatory cells in muscle, regardless of whether overt histological signs of injury are apparent.


2016 ◽  
Vol 311 (4) ◽  
pp. C607-C615 ◽  
Author(s):  
Lawrence M. Schwartz ◽  
Christine Brown ◽  
Kevin McLaughlin ◽  
Wendy Smith ◽  
Carol Bigelow

Skeletal muscle mass can increase during hypertrophy or decline dramatically in response to normal or pathological signals that trigger atrophy. Many reports have documented that the number of nuclei within these cells is also plastic. It has been proposed that a yet-to-be-defined regulatory mechanism functions to maintain a relatively stable relationship between the cytoplasmic volume and nuclear number within the cell, a phenomenon known as the “myonuclear domain” hypothesis. While it is accepted that hypertrophy is typically associated with the addition of new nuclei to the muscle fiber from stem cells such as satellite cells, the loss of myonuclei during atrophy has been controversial. The intersegmental muscles from the tobacco hawkmoth Manduca sexta are composed of giant syncytial cells that undergo sequential developmental programs of atrophy and programmed cell death at the end of metamorphosis. Since the intersegmental muscles lack satellite cells or regenerative capacity, the tissue is not “contaminated” by these nonmuscle nuclei. Consequently, we monitored muscle mass, cross-sectional area, nuclear number, and cellular DNA content during atrophy and the early phases of cell death. Despite a ∼75–80% decline in muscle mass and cross-sectional area during the period under investigation, there were no reductions in nuclear number or DNA content, and the myonuclear domain was reduced by ∼85%. These data suggest that the myonuclear domain is not an intrinsic property of skeletal muscle and that nuclei persist through atrophy and programmed cell death.


Nutrients ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 2647
Author(s):  
Francisco José Sánchez-Torralvo ◽  
Ignacio Ruiz-García ◽  
Victoria Contreras-Bolívar ◽  
Inmaculada González-Almendros ◽  
María Ruiz-Vico ◽  
...  

Our objective was to evaluate the clinical application of third lumbar vertebra (L3)-computer tomography (CT)-determined sarcopenia as a marker of muscle mass in cancer inpatients diagnosed with malnutrition according to the Global Leadership Initiative on Malnutrition (GLIM) criteria and to establish its association with 6-month mortality. Methods: This was an observational, prospective study in patients from an inpatient oncology unit. We performed a nutritional assessment according to GLIM criteria, including muscle cross-sectional area at L3 by CT and skeletal muscle index (SMI). Six-month mortality was evaluated. Results: A total of 208 patients were included. The skeletal muscle cross-sectional area at L3 was 136.2 ± 32.5 cm2 in men and 98.1 ± 21.2 cm2 in women. The SMI was 47.4 ± 12.3 cm2/m2 in men and 38.7 ± 8.3 cm2/m2 in women. Sarcopenia (low SMI) was detected in 59.6% of the subjects. Using SMI as a marker of low muscle mass in application of GLIM criteria, we found 183 (87.9%) malnourished patients. There were 104 deaths (50%) at 6 months. The deceased patients had a lower skeletal muscle cross-sectional area (112.9 ± 27.9 vs. 126.1 ± 37.8 cm2; p = 0.003) and a lower SMI (41.3 ± 9.5 vs. 45.7 ± 12.9 cm2/m2; p = 0.006). An increased risk of 6-month mortality was found in malnourished patients according to GLIM criteria using SMI (HR 2.47; 95% confidence interval 1.07–5.68; p = 0.033). Conclusions: Low muscle mass, assessed by L3-CT, was observed to affect more than half of cancer inpatients. The deceased patients at 6 months had a lower skeletal muscle cross-sectional area and SMI. Malnutrition according to GLIM criteria using CT-determined sarcopenia was shown to adequately predict 6-month mortality.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3322-3322
Author(s):  
Yasuhiko Shibasaki ◽  
Kenta Kobayashi ◽  
Tatsuya Suwabe ◽  
Kyoko Fuse ◽  
Miwako Narita ◽  
...  

Introduction Depletion of skeletal muscle is a poor prognostic factor for patients with various malignancies; however its significance for allogeneic hematopoietic cell transplantation (allo-HCT) in patients with hematological disease is unclear. Generally, muscle mass is measured by the methods established by the European Working Group on Sarcopenia in Older People, which require the use of dual energy X-ray absorptiometry or bioimpedance analysis, methods that are not performed in routine practice. Therefore, cross-sectional imaging using computed tomography (CT) has been suggested as an alternative method for analyzing muscle mass in clinical practice. Especially, lumbar total muscle cross-sectional area using CT, normalized for body height, which was named lumbar skeletal muscle mass index (SMI), is reported as an indicator of nutritional status, sarcopenia and cancer cachexia in patients with solid organ malignancy. Aims To clarify the usefulness of a pre-transplant lumber SMI as a prognostic indicator for allo-HCT patients. Methods Among 208 patients with hematological disease who underwent allo-HCT between 2006 and 2017 at our facility, 191 patients (95 males and 96 females) underwent CT scans for routine pre-transplant status assessment. Ninety patients had acute myeloid leukemia, 38 patients had acute lymphoblastic leukemia, 24 patients had myelodysplastic syndrome, 20 patients had malignant lymphoma, and 19 patients had other diseases. The median age of the patients was 42 years old (range: 16-66 years). Seventy-eight patients received myeloablative conditioning and the others received reduced intensity conditioning regimens. The number of patients in each HCT-comorbidity index (HCT-CI) risk group was as follows: low: 72, intermediate: 54 and high: 65. Axial images at the iliac crest were selected for analysis of lumber total muscle cross-sectional area (cm2). The rectus abdominus, psoas and paraspinal muscles were identified and quantified. Lumbar total muscle cross-sectional area was normalized for body height in meters squared (m2) and used to calculate lumbar SMI (cm2/m2). This study was performed in accordance with the Japanese Ethical Guidelines for Medical and Health Research Involving Humans and approved by the Ethical Committee of our facility. Results The median pre-transplant lumber SMI of the male patients was significantly higher than that of the female patients (42.7 (24.9-60.2) mm2/m2 vs. 31.9 (20.7-44.6) mm2/m2, p<0.01). We defined the cutoff value of lumber SMI as 42.7cm2/m2 for male and 31.9cm2/m2 for female patients. In the Kaplan-Meier estimate analysis, low lumber SMI was a significant poor prognostic factor for overall survival (p=0.016). In multivariate analysis using Cox regression model, adjusting for age, refined disease risk index, conditioning and HCT-CI, low lumber SMI was extracted as a significant poor prognostic factor for overall survival (hazard ratio 1.56, 95% confidence interval (CI) 1.03-2.36, p=0.036). By logistic regression analysis, adjusted odds ratio of 1-year non-relapse mortality for low lumber SMI was 2.47 (95% CI 1.13-5.41, p=0.024). Conclusion Low pre-transplant lumber SMI is a significant poor prognostic factor in allo-HCT, independent of other risk factors including HCT-CI and refined disease risk index in patients with hematological disease. It is affected by the high rate of non-relapse mortality in the early phase following allo-HCT in patients with low lumber SMI. Disclosures No relevant conflicts of interest to declare.


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