scholarly journals Molecular mechanisms underlying skeletal muscle weakness in human cancer: reduced myosin-actin cross-bridge formation and kinetics

2013 ◽  
Vol 114 (7) ◽  
pp. 858-868 ◽  
Author(s):  
Michael J. Toth ◽  
Mark S. Miller ◽  
Damien M. Callahan ◽  
Andrew P. Sweeny ◽  
Ivette Nunez ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Weakness ◽  
Physical Disability ◽  
Human Cancer ◽  
Knee Extensor ◽  
Whole Body ◽  
Mhc I ◽  
Patients With Cancer ◽  
Cross Bridge ◽  
Isometric Torque

Many patients with cancer experience physical disability following diagnosis, although little is known about the mechanisms underlying these functional deficits. To characterize skeletal muscle adaptations to cancer in humans, we evaluated skeletal muscle structure and contractile function at the molecular, cellular, whole-muscle, and whole-body level in 11 patients with cancer (5 cachectic, 6 noncachectic) and 6 controls without disease. Patients with cancer showed a 25% reduction in knee extensor isometric torque after adjustment for muscle mass ( P < 0.05), which was strongly related to diminished power output during a walking endurance test ( r = 0.889; P < 0.01). At the cellular level, single fiber isometric tension was reduced in myosin heavy chain (MHC) IIA fibers ( P = 0.05) in patients with cancer, which was explained by a reduction ( P < 0.05) in the number of strongly bound cross-bridges. In MHC I fibers, myosin-actin cross-bridge kinetics were reduced in patients, as evidenced by an increase in myosin attachment time ( P < 0.01); and reductions in another kinetic parameter, myosin rate of force production, predicted reduced knee extensor isometric torque ( r = 0.689; P < 0.05). Patients with cancer also exhibited reduced mitochondrial density (−50%; P < 0.001), which was related to increased myosin attachment time in MHC I fibers ( r = −0.754; P < 0.01). Finally, no group differences in myofilament protein content or ultrastructure were noted that explained the observed functional alterations. Collectively, our results suggest reductions in myofilament protein function as a potential molecular mechanism contributing to muscle weakness and physical disability in human cancer.

Skeletal muscle mitochondrial dysfunction and muscle and whole-body functional deficits in cancer patients with weight loss

2021 ◽  
Author(s):  
Hawley E. Kunz ◽  
John D. Port ◽  
Kenton R. Kaufman ◽  
Aminah Jatoi ◽  
Corey R. Hart ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Weight Loss ◽  
Mitochondrial Function ◽  
Protein Turnover ◽  
Knee Extensor ◽  
Whole Body ◽  
Lower State ◽  
Body Protein ◽  
Atp Production ◽  
Patients With Cancer

Reductions in skeletal muscle mass and function are often reported in patients with cancer-associated weight loss and are associated with reduced quality of life, impaired treatment tolerance, and increased mortality. Although cellular changes, including altered mitochondrial function, have been reported in animals, such changes have been incompletely characterized in humans with cancer. Whole body and skeletal muscle physical function, skeletal muscle mitochondrial function and whole-body protein turnover were assessed in 8 patients with cancer-associated weight loss (10.1±4.2% body weight over 6-12 months) and 19 age-, sex-, and BMI-matched healthy controls to characterize skeletal muscle changes at the whole body, muscle, and cellular level. Potential pathways involved in cancer-induced alterations in metabolism and mitochondrial function were explored by interrogating skeletal muscle and plasma metabolomes. Despite similar lean mass compared to control participants, patients with cancer exhibited reduced habitual physical activity (57% fewer daily steps), cardiorespiratory fitness (22% lower VO2peak [mL/kg/min]) and leg strength (35% lower isokinetic knee extensor strength) and greater leg neuromuscular fatigue (36% greater decline in knee extensor torque). Concomitant with these functional declines, patients with cancer had lower mitochondrial oxidative capacity (25% lower State 3 O2 flux [pmol/s/mg tissue]) and ATP production (23% lower State 3 ATP production [pmol/s/mg tissue]) and alterations in phospholipid metabolite profiles indicative of mitochondrial abnormalities. Whole body protein turnover was unchanged. These findings demonstrate mitochondrial abnormalities concomitant with whole-body and skeletal muscle functional derangements associated with human cancer, supporting future work studying the role of mitochondria in the muscle deficits associated with cancer.

Corticosteroids and skeletal muscle function in cystic fibrosis

2003 ◽  
Vol 95 (4) ◽  
pp. 1379-1384 ◽  
Author(s):  
Sinead C. Barry ◽  
Charles G. Gallagher
Keyword(s):  
Skeletal Muscle ◽  
Cystic Fibrosis ◽  
Muscle Strength ◽  
Muscle Weakness ◽  
Muscle Function ◽  
Knee Extensor ◽  
Skeletal Muscle Function ◽  
Peripheral Muscle ◽  
Causative Effect ◽  
Concomitant Medications

Patients with cystic fibrosis (CF) have reduced peripheral muscle strength. We tested the hypothesis that steroid treatment contributes to muscle weakness in adults with CF. Twenty-three stable CF patients were studied. Measurements included knee extensor (KE), knee flexor (KF), elbow flexor (EF), handgrip (HG), expiratory (Pemax), and inspiratory (Pimax) muscle strengths. Spirometry, body mass index (BMI), and days spent in hospital over the preceding 12 mo (DH) were also measured. Average daily dose of prednisolone over the preceding 12 mo (ADD) was 5.1 mg/day. Pearson's correlation analysis revealed that ADD correlated significantly with skeletal muscle strengths (KF%, r = -0.63, P < 0.01) with the exception of HG%. These findings are independent of age, BMI, pulmonary function, and DH. Multiple-regression analysis revealed that ADD was the most significant predictor of all measures of skeletal muscle function except HG%. It was independently responsible for 54% of the variance in Pimax%, for 46% of the variance in Pemax%, for 45% of the variance in KE%, for 39% of the variance in KF%, and for 41% of the variance in EF%. Concomitant medications (e.g., theophylline) were shown to have no causative effect. Corticosteroids contribute to the skeletal muscle weakness seen in CF patients. The correlation of proximal muscle strength, but not HG strength, with steroid dosage further supports a cause-effect relationship.

Spatial and temporal variability of intratumoral 18F-FDG distribution in patients with cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e21149-e21149
Author(s):  
Aashish D. Bhatt ◽  
Xiao-Feng Li ◽  
Geetika Bhatt ◽  
Goetz H. Kloecker ◽  
Vivek R. Sharma ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Human Cancer ◽  
Whole Body ◽  
Ct Scans ◽  
Spatial And Temporal Variability ◽  
Fdg Uptake ◽  
Patients With Cancer ◽  
Spatial Changes ◽  
Pet Ct ◽  
Wide Range

e21149 Background: We previously reported that in mice models, tumor microenvironment is complex and intratumoral 18F-FDG distribution is heterogeneous. There were apparent spatial and temporal intratumoral 18F-FDG distribution changes occurring even within 24-48 hour interval in human cancer cell xenografts grown in nude mice. We hypothesized that what was documented in mice models may also be applicable to human patients with cancer. The objective of this study was to investigate the intratumoral spatial and temporal distribution of 18F-FDG in cancer patients. Methods: Five patients who had repeat PET/CT scans within 1-28 days and with no interval therapy were identified. All patients had fasted overnight and had blood glucose level of less than 200 mg/dl. They were injected with 8.0-14.0mCi of 18F-FDG intravenously, and whole body PET/CT scans were performed 60-80 minutes later utilizing a Siemens PET/CT scanner. Each patient’s intratumoral FDG activity distributions were mapped and compared to each other utilizing magnified digital images of the tumors. Results: Intratumoral FDG activity is very heterogeneous. Within the same tumor, there is a wide range of high and low FDG uptake variations. Apparent change in intratumoral FDG distribution was found within as short as a 24 hour interval in the same patient. Although the global tumoral FDG activity and liver FDG activity measured as SUVmaximum and SUVaverage were not significantly different from one PET/CT to another, there were significant spatial changes and variations of the tumor FDG activity between the two PET/CT images. Conclusions: Intratumoral 18F-FDG uptake is very heterogeneous and manifests both temporal and spatial changes within as short as 24 hours even in untreated cancer patients. This should be taken into consideration during FDG PET based therapy decisions, for example in tumor and nodal staging or radiation therapy planning.

The use of alternate vertebral levels to L3 in computed tomography scans for skeletal muscle mass evaluation and sarcopenia assessment in patients with cancer: a systematic review

2021 ◽  
pp. 1-49
Author(s):  
Belinda Vangelov ◽  
Judy Bauer ◽  
Damian Kotevski ◽  
Robert I. Smee
Keyword(s):  
Computed Tomography ◽  
Skeletal Muscle ◽  
Ct Scan ◽  
Cancer Patients ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Whole Body ◽  
Ct Scans ◽  
Cross Sectional ◽  
Patients With Cancer

ABSTRACT Body composition measurement using diagnostic computed tomography (CT) scans has emerged as a method to assess sarcopenia (low muscle mass) in oncology patients. Assessment of skeletal muscle mass (SMM) using the cross-sectional area (CSA) of a single vertebral slice (at lumbar L3) in a CT scan is correlated to whole body skeletal muscle volume. This method is used to assess CT-defined sarcopenia in patients with cancer, with low SMM effecting outcomes. However, as diagnostic scans are based on tumour location, not all include L3. We evaluated the evidence for the use of alternate vertebral CT slices for SMM evaluation when L3 is not available. Five electronic databases were searched from Jan 1996-April 2020 for studies using CT scan vertebral slices above L3 for SM measurement in adults with cancer (solid tumours). Validation with whole body SMM, rationale for the chosen slice, and sarcopenia cut-off values were investigated. Thirty-two studies were included, all retrospective and cross-sectional in design. Cervical, thoracic, and lumbar slices were used (from C3-L1), with no validation of whole body SMM using CT scans. Alternate slices were used in lung, and head and neck cancer patients. Sarcopenia cut-off values were reported in 75% of studies, with differing methods, with or without sex-specific values, and a lack of consensus. Current evidence is inadequate to provide definitive recommendations for alternate vertebral slice use for SMM evaluation in cancer patients. Variation in sarcopenia cut-offs warrants more robust investigation, in order for risk stratification to be applied to all patients with cancer.

scholarly journals Mobility Interventions to Improve Outcomes in Patients Undergoing Prolonged Mechanical Ventilation: A Review of the Literature

2008 ◽  
Vol 10 (1) ◽  
pp. 21-33 ◽  
Author(s):  
JiYeon Choi ◽  
Frederick J. Tasota ◽  
Leslie A. Hoffman
Keyword(s):  
Skeletal Muscle ◽  
Mechanical Ventilation ◽  
Critical Illness ◽  
Muscle Weakness ◽  
Functional Ability ◽  
Prolonged Mechanical Ventilation ◽  
Adverse Outcomes ◽  
Whole Body ◽  
Multicenter Studies ◽  
Skeletal Muscle Weakness

Survivors of critical illness often undergo an extended recovery trajectory. Reduced functional ability is one of several adverse outcomes of prolonged bed rest and mechanical ventilation during critical illness. Skeletal muscle weakness is known to be one of the major phenomena that account for reduced functional ability. Although skeletal muscle weakness is evident after prolonged mechanical ventilation (PMV), few studies have tested the benefits of various types of mobility interventions in this population. The purpose of this article is to review the published research on improving mobility outcomes in patients undergoing PMV. For this review, published studies were retrieved from MEDLINE, PubMed, CINAHL, and the Cochrane Database of Systematic Reviews from January 1990 to July 2007. A total of 10 relevant articles were selected that examined the effect of whole body physical therapy, electrical stimulation (ES), arm exercise, and inspiratory muscle training (IMT). Overall, there is support for the ability of mobility interventions to improve outcomes in patients on PMV but limited evidence of how to best accomplish this goal. Generating more data from multicenter studies and randomized controlled trials is recommended.

scholarly journals Resistance training rejuvenates the mitochondrial methylome in aged human skeletal muscle

2021 ◽  
Author(s):  
Bradley A. Ruple ◽  
Joshua S. Godwin ◽  
Paulo H.C. Mesquita ◽  
Shelby C. Osburn ◽  
Christopher G. Vann ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Resistance Training ◽  
Nuclear Dna ◽  
Vastus Lateralis ◽  
Knee Extensor ◽  
Complex Iii ◽  
Whole Body ◽  
Cpg Sites ◽  
Extensor Torque ◽  
Older Males

Resistance training (RT) alters skeletal muscle nuclear DNA methylation patterns (or the methylome). However, no study has examined if RT affects the mitochondrial DNA (mtDNA) methylome. Herein, ten older untrained males (65+/-7 years old) performed six weeks of full-body RT (twice weekly). Body composition and knee extensor torque were assessed prior to and 72 hours following the last RT session. Vastus lateralis (VL) biopsies were also obtained. VL DNA was subjected to reduced representation bisulfite sequencing providing excellent coverage across the ~16-kilobase mtDNA methylome (254 CpG sites). Various biochemical assays were also performed, and older male data were compared to younger trained males (22+/-2 years old, n=7). RT increased whole-body lean tissue mass (p=0.017), VL thickness (p=0.012), and knee extensor torque (p=0.029) in older males. RT also profoundly affected the mtDNA methylome in older males, as 63% (159/254) of the CpG sites demonstrated reduced methylation (p<0.05). Notably, several mtDNA sites presented a more youthful signature after RT in older males when comparisons were made to younger males. The 1.12 kilobase D-loop/control region on mtDNA, which regulates mtDNA replication and transcription, possessed enriched hypomethylation in older males following RT. Enhanced expression of mitochondrial H- and L-strand genes and increases in mitochondrial complex III and IV protein levels were also observed (p<0.05). This is the first study to show RT alters the mtDNA methylome in skeletal muscle. Observed methylome alterations may enhance mitochondrial transcription, and RT remarkably evokes mitochondrial methylome profiles to mimic a more youthful signature in older males.

scholarly journals Sex-Dependent Effects of Quadriceps Fat Content on Single Muscle Fiber Size in Older Adults

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 127-128
Author(s):  
Chad Straight ◽  
Joseph Gordon ◽  
Aurora Foster ◽  
Nicholas Remillard ◽  
Bruce Damon ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Older Women ◽  
Muscle Fiber ◽  
Vigorous Physical Activity ◽  
Knee Extensor ◽  
Single Fiber ◽  
Type I ◽  
Cross Bridge ◽  
Fiber Size ◽  
And Function

Abstract Evidence suggests that ectopic fat deposition interferes with skeletal muscle structure and function, but few studies have examined underlying morphological and contractile properties at the single fiber level. Healthy older (65-75 y) men (n=9) and women (n=9) underwent dynamometry for assessment of knee extensor maximal torque, water-fat magnetic resonance imaging to quantify quadriceps muscle cross-sectional area (CSA) and fat fraction (FF), and vastus lateralis biopsies to determine morphology and function of type I and II muscle fibers. Despite similar body mass indices (24.4±1.3 vs. 24.6±0.5 kg∙m2, p=0.93) and daily moderate-to-vigorous physical activity (46±7 vs. 41±9 min∙d-1, p=0.67), women had greater FF (9.0±0.3 [range: 7.6-10.6] vs. 7.9±0.4 [6.0-9.7] %, p=0.04) than men, indicating increased adipose tissue deposition in skeletal muscle. Women also had smaller quadriceps CSA (39.8±1.8 vs. 57.9±1.3 cm2, p=0.01), specific torque (1.5±0.1 vs. 1.9±0.1 Nm∙cm-2, p=0.01) and type II fiber CSA (3,943±312 [2,350-5,140] vs. 5,352±384 [3,560-6,590] µm2, p=0.01) than men. Type I CSA did not differ by sex (4,918±228 [3,740-5,600] vs. 5,630±440 [3,640-7,670] µm2, p=0.19). In older women, FF was inversely associated with single fiber CSA in type I (r= -0.81, p=0.02) and II (r= -0.76, p=0.03) fibers, and tended to be associated with slower myosin-actin cross-bridge kinetics (longer myosin attachment time) in type I fibers (r=0.65, p=0.08). These relationships were not observed in men. Overall, healthy older women have greater intramuscular fat than men, which may contribute to sex-specific effects on knee extensor specific torque through differences in muscle fiber size and cross-bridge kinetics.

scholarly journals Age-related slowing of myosin actin cross-bridge kinetics is sex specific and predicts decrements in whole skeletal muscle performance in humans

2013 ◽  
Vol 115 (7) ◽  
pp. 1004-1014 ◽  
Author(s):  
Mark S. Miller ◽  
Nicholas G. Bedrin ◽  
Damien M. Callahan ◽  
Michael J. Previs ◽  
Mark E. Jennings ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Physical Disability ◽  
Isometric Tension ◽  
Single Fiber ◽  
Muscle Dysfunction ◽  
Myosin Molecule ◽  
Cross Bridge ◽  
Skeletal Muscle Dysfunction ◽  
Age Related ◽  
Whole Muscle

We hypothesize that age-related skeletal muscle dysfunction and physical disability may be partially explained by alterations in the function of the myosin molecule. To test this hypothesis, skeletal muscle function at the whole muscle, single fiber, and molecular levels was measured in young (21–35 yr) and older (65–75 yr) male and female volunteers with similar physical activity levels. After adjusting for muscle size, older adults had similar knee extensor isometric torque values compared with young, but had lower isokinetic power, most notably in women. At the single-fiber and molecular levels, aging was associated with increased isometric tension, slowed myosin actin cross-bridge kinetics (longer myosin attachment times and reduced rates of myosin force production), greater myofilament lattice stiffness, and reduced phosphorylation of the fast myosin regulatory light chain; however, the age effect was driven primarily by women (i.e., age-by-sex interaction effects). In myosin heavy chain IIA fibers, single-fiber isometric tension and molecular level mechanical and kinetic indexes were correlated with whole muscle isokinetic power output. Collectively, considering that contractile dysfunction scales up through various anatomical levels, our results suggest a potential sex-specific molecular mechanism, reduced cross-bridge kinetics, contributes to the reduced physical capacity with aging in women. Thus these results support our hypothesis that age-related alterations in the myosin molecule contribute to skeletal muscle dysfunction and physical disability and indicate that this effect is stronger in women.

Tropomyosin mutations responsible for muscle weakness in inherited skeletal muscle diseases

2008 ◽  
pp. 20-21
Author(s):  
Julien Ochala ◽  
Anders Oldfors ◽  
Lars Larsson
Keyword(s):  
Skeletal Muscle ◽  
Muscle Weakness ◽  
Muscle Diseases

Neural control of glucose uptake by skeletal muscle after central administration of NMDA

1995 ◽  
Vol 268 (2) ◽  
pp. R492-R497 ◽  
Author(s):  
C. H. Lang ◽  
M. Ajmal ◽  
A. G. Baillie
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Glucose Uptake ◽  
Neural Control ◽  
Plasma Insulin ◽  
Regional Blood Flow ◽  
Muscle Blood Flow ◽  
Whole Body ◽  
Glucose Disposal ◽  
Central Administration

Intracerebroventricular injection of N-methyl-D-aspartate (NMDA) produces hyperglycemia and increases whole body glucose uptake. The purpose of the present study was to determine in rats which tissues are responsible for the elevated rate of glucose disposal. NMDA was injected intracerebroventricularly, and the glucose metabolic rate (Rg) was determined for individual tissues 20-60 min later using 2-deoxy-D-[U-14C]glucose. NMDA decreased Rg in skin, ileum, lung, and liver (30-35%) compared with time-matched control animals. In contrast, Rg in skeletal muscle and heart was increased 150-160%. This increased Rg was not due to an elevation in plasma insulin concentrations. In subsequent studies, the sciatic nerve in one leg was cut 4 h before injection of NMDA. NMDA increased Rg in the gastrocnemius (149%) and soleus (220%) in the innervated leg. However, Rg was not increased after NMDA in contralateral muscles from the denervated limb. Data from a third series of experiments indicated that the NMDA-induced increase in Rg by innervated muscle and its abolition in the denervated muscle were not due to changes in muscle blood flow. The results of the present study indicate that 1) central administration of NMDA increases whole body glucose uptake by preferentially stimulating glucose uptake by skeletal muscle, and 2) the enhanced glucose uptake by muscle is neurally mediated and independent of changes in either the plasma insulin concentration or regional blood flow.

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