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.

Whole-body protein turnover in metabolically stressed patients and patients with cancer as measured with [15N] glycine

1983 ◽  
Vol 30 (1) ◽  
pp. 59-77 ◽  
Author(s):  
T.P. Stein ◽  
S.D. Ang ◽  
M.D. Schluter ◽  
M.J. Leskiw ◽  
M. Nusbaum
Keyword(s):  
Protein Turnover ◽  
Whole Body ◽  
Body Protein ◽  
Patients With Cancer

Effect of glycogen availability on human skeletal muscle protein turnover during exercise and recovery

2010 ◽  
Vol 109 (2) ◽  
pp. 431-438 ◽  
Author(s):  
Krista R. Howarth ◽  
Stuart M. Phillips ◽  
Maureen J. MacDonald ◽  
Douglas Richards ◽  
Natalie A. Moreau ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Protein Turnover ◽  
Muscle Protein ◽  
Whole Body ◽  
Skeletal Muscle Protein ◽  
Protein Balance ◽  
Body Protein ◽  
Muscle Protein Turnover ◽  
Net Protein

We examined the effect of carbohydrate (CHO) availability on whole body and skeletal muscle protein utilization at rest, during exercise, and during recovery in humans. Six men cycled at ∼75% peak O2 uptake (V̇o2peak) to exhaustion to reduce body CHO stores and then consumed either a high-CHO (H-CHO; 71 ± 3% CHO) or low-CHO (L-CHO; 11 ± 1% CHO) diet for 2 days before the trial in random order. After each dietary intervention, subjects received a primed constant infusion of [1-13C]leucine and l-[ring-2H5]phenylalanine for measurements of the whole body net protein balance and skeletal muscle protein turnover. Muscle, breath, and arterial and venous blood samples were obtained at rest, during 2 h of two-legged kicking exercise at ∼45% of kicking V̇o2peak, and during 1 h of recovery. Biopsy samples confirmed that the muscle glycogen concentration was lower in the L-CHO group versus the H-CHO group at rest, after exercise, and after recovery. The net leg protein balance was decreased in the L-CHO group compared with at rest and compared with the H-CHO condition, which was primarily due to an increase in protein degradation (area under the curve of the phenylalanine rate of appearance: 1,331 ± 162 μmol in the L-CHO group vs. 786 ± 51 μmol in the H-CHO group, P < 0.05) but also due to a decrease in protein synthesis late in exercise. There were no changes during exercise in the rate of appearance compared with rest in the H-CHO group. Whole body leucine oxidation increased above rest in the L-CHO group only and was higher than in the H-CHO group. The whole body net protein balance was reduced in the L-CHO group, largely due to a decrease in whole body protein synthesis. These data extend previous findings by others and demonstrate, using contemporary stable isotope methodology, that CHO availability influences the rates of skeletal muscle and whole body protein synthesis, degradation, and net balance during prolonged exercise in humans.

A ketogenic diet combined with exercise alters mitochondrial function in human skeletal muscle while improving metabolic health

2020 ◽  
Vol 319 (6) ◽  
pp. E995-E1007 ◽  
Author(s):  
Vincent J. Miller ◽  
Richard A. LaFountain ◽  
Emily Barnhart ◽  
Teryn S. Sapper ◽  
Jay Short ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Ketogenic Diet ◽  
Mitochondrial Function ◽  
Metabolic Health ◽  
Whole Body ◽  
Model Assessment ◽  
Atp Production ◽  
Ketogenic Diets ◽  
Supervised Exercise

Animal data indicate that ketogenic diets are associated with improved mitochondrial function, but human data are lacking. We aimed to characterize skeletal muscle mitochondrial changes in response to a ketogenic diet combined with exercise training in healthy individuals. Twenty-nine physically active adults completed a 12-wk supervised exercise program after self-selection into a ketogenic diet (KD, n = 15) group or maintenance of their habitual mixed diet (MD, n = 14). Measures of metabolic health and muscle biopsies (vastus lateralis) were obtained before and after the intervention. Mitochondria were isolated from muscle and studied after exposure to carbohydrate (pyruvate), fat (palmitoyl-l-carnitine), and ketone (β-hydroxybutyrate+acetoacetate) substrates. Compared with MD, the KD resulted in increased whole body resting fat oxidation ( P < 0.001) and decreased fasting insulin ( P = 0.019), insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR), P = 0.022], and visceral fat ( P < 0.001). The KD altered mitochondrial function as evidenced by increases in mitochondrial respiratory control ratio (19%, P = 0.009), ATP production (36%, P = 0.028), and ATP/H2O2 (36%, P = 0.033) with the fat-based substrate. ATP production with the ketone-based substrate was four to eight times lower than with other substrates, indicating minimal oxidation. The KD resulted in a small decrease in muscle glycogen (14%, P = 0.035) and an increase in muscle triglyceride (81%, P = 0.006). These results expand our understanding of human adaptation to a ketogenic diet combined with exercise. In conjunction with weight loss, we observed altered skeletal muscle mitochondrial function and efficiency, an effect that may contribute to the therapeutic use of ketogenic diets in various clinical conditions, especially those associated with insulin resistance.

Skeletal muscle and whole body protein turnover in thyroid disease

1988 ◽  
Vol 18 (1) ◽  
pp. 62-68 ◽  
Author(s):  
W. L. MORRISON ◽  
J. N. A. GIBSON ◽  
R. T. JUNG ◽  
M. J. RENNIE
Keyword(s):  
Skeletal Muscle ◽  
Thyroid Disease ◽  
Protein Turnover ◽  
Whole Body ◽  
Body Protein

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.

scholarly journals Measuring Protein Turnover in the Field: Implications for Military Research

2020 ◽  
Author(s):  
Katrina L Hinde ◽  
Thomas J O'Leary ◽  
Julie P Greeves ◽  
Sophie L Wardle
Keyword(s):  
Skeletal Muscle ◽  
Protein Turnover ◽  
Muscle Protein ◽  
Military Training ◽  
Field Research ◽  
Whole Body ◽  
Skeletal Muscle Protein ◽  
Free Living ◽  
Body Protein ◽  
Product Method

ABSTRACT Protein turnover reflects the continual synthesis and breakdown of body proteins, and can be measured at a whole-body (i.e. aggregated across all body proteins) or tissue (e.g. skeletal muscle only) level using stable isotope methods. Evaluating protein turnover in free-living environments, such as military training, can help inform protein requirements. We undertook a narrative review of published literature with the aim of reviewing the suitability of, and advancements in, stable isotope methods for measuring protein turnover in field research. The 2 primary approaches for measuring protein turnover are based on precursor- and end-product methods. The precursor method is the gold-standard for measuring acute (over several hours) skeletal muscle protein turnover, whereas the end-product method measures chronic (over several weeks) skeletal muscle protein turnover and provides the opportunity to monitor free-living activities. Both methods require invasive procedures such as the infusion of amino acid tracers and muscle biopsies to assess the uptake of the tracer into tissue. However, the end-product method can also be used to measure acute (over 9–24 h) whole-body protein turnover noninvasively by ingesting 15N-glycine, or equivalent isotope tracers, and collecting urine samples. The end-product method using 15N-glycine is a practical method for measuring whole-body protein turnover in the field over short (24 h) time frames and has been used effectively in recent military field research. Application of this method may improve our understanding of protein kinetics during conditions of high physiological stress in free-living environments such as military training.

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