Oxidative capacity and ageing in human muscle. Improving the vitamin D status of vitamin D deficient adults is associated with improved mitochondrial oxidative function in skeletal muscle. The Effect of Neoadjuvant Chemoradiotherapy on Whole-Body Physical Fitness and Skeletal Muscle Mitochondrial Oxidative Phosphorylation In Vivo in Locally Advanced Rectal Cancer Patients – An Observational Pilot Study Higher mitochondrial respiration and uncoupling with reduced electron transport chain content in vivo in muscle of sedentary versus active subjects.
This study determined the decline in oxidative capacity per volume of human vastus lateralis muscle between nine adult ( mean age 38.8 years ) and 40 elderly ( mean age 68.8 years ) human subjects ( age range 25 - 80 years ) . We based our oxidative capacity estimates on the kinetics of changes in creatine phosphate content ( [ PCr ] ) during recovery from exercise as measured by (31)P magnetic resonance ( MR ) spectroscopy . A matched muscle biopsy sample permitted determination of mitochondrial volume density and the contribution of the loss of mitochondrial content to the decline in oxidative capacity with age . The maximal oxidative phosphorylation rate or oxidative capacity was estimated from the PCr recovery rate constant ( k(PCr ) ) and the [ PCr ] in accordance with a simple electrical circuit model of mitochondrial respiratory control . Oxidative capacity was 50 % lower in the elderly vs. the adult group ( 0.61 + /- 0.04 vs. 1.16 + /- 0.147 mM ATP s(-1 ) ) . Mitochondrial volume density was significantly lower in elderly compared with adult muscle ( 2.9 + /- 0.15 vs. 3.6 + /- 0.11 % ) . In addition , the oxidative capacity per mitochondrial volume ( 0.22 + /- 0.042 vs. 0.32 + /- 0.015 mM ATP ( s % ) ( -1 ) ) was reduced in elderly vs. adult subjects . This study showed that elderly subjects had nearly 50 % lower oxidative capacity per volume of muscle than adult subjects . The cellular basis of this drop was a reduction in mitochondrial content , as well as a lower oxidative capacity of the mitochondria with age OBJECTIVE Suboptimal mitochondrial function has been implicated in several disorders in which fatigue is a prominent feature . Vitamin D deficiency is a well-recognized cause of fatigue and myopathy . The aim of this study was to examine the effects of cholecalciferol therapy on skeletal mitochondrial oxidative function in symptomatic , vitamin D-deficient individuals . DESIGN This longitudinal study assessed mitochondrial oxidative phosphorylation in the gastrosoleus compartment using phosphorus-31 magnetic resonance spectroscopy measurements of phosphocreatine recovery kinetics in 12 symptomatic , severely vitamin D-deficient subjects before and after treatment with cholecalciferol .  All subjects had serum assays before and after cholecalciferol therapy to document serum 25-hydroxyvitamin D ( 25OHD ) and bone profiles . Fifteen healthy controls also underwent (31)P-magnetic resonance spectroscopy and serum 25OHD assessment . RESULTS The phosphocreatine recovery half-time ( τ1/2PCr ) was significantly reduced after cholecalciferol therapy in the subjects indicating an improvement in maximal oxidative phosphorylation ( 34.44 ± 8.18 sec to 27.84 ± 9.54 sec , P < .001 ) . This was associated with an improvement in mean serum 25OHD levels ( 8.8 ± 4.2 nmol/L to 113.8 ± 51.5 nmol/L , P < .001 ) . There was no difference in phosphate metabolites at rest . A linear regression model showed that decreasing serum 25OHD levels was associated with increasing τ1/2PCr ( r = -0.41 , P = .009 ) . All patients reported an improvement in fatigue  after cholecalciferol therapy . CONCLUSIONS Cholecalciferol therapy augments muscle mitochondrial maximal oxidative phosphorylation after exercise in symptomatic , vitamin D-deficient individuals . This finding suggests that changes in mitochondrial oxidative phosphorylation in skeletal muscle could at least be partly responsible for the fatigue experienced by these patients . For the first time , we demonstrate a link between vitamin D and the mitochondria in human skeletal muscle Background In the United Kingdom , patients with locally advanced rectal cancer routinely receive neoadjuvant chemoradiotherapy . However , the effects of this on physical fitness are unclear . This pilot study is aim ed to investigate the effect of neoadjuvant chemoradiotherapy on objective ly measured in vivo muscle mitochondrial function and whole-body physical fitness . Methods We prospect ively studied 12 patients with rectal cancer who completed st and ardized neoadjuvant chemoradiotherapy , recruited from a large tertiary cancer centre , between October 2012 and July 2013 . All patients underwent a cardiopulmonary exercise test and a phosphorus magnetic resonance spectroscopy quadriceps muscle exercise-recovery study before and after neoadjuvant chemoradiotherapy . Data were analysed and reported blind to patient identity and clinical course . Primary variables of interest were the two physical fitness measures ; oxygen uptake at estimated anaerobic threshold and oxygen uptake at Peak exercise ( ml.kg−1.min−1 ) , and the post-exercise phosphocreatine recovery rate constant ( min−1 ) , a measure of muscle mitochondrial capacity in vivo .  Results Median age was 67 years ( IQR 64–75 ) . Differences ( 95%CI ) in all three primary variables were significantly negative post-NACRT : Oxygen uptake at estimated anaerobic threshold −2.4 ml.kg−1.min−1 ( −3.8 , −0.9 ) , p = 0.004 ; Oxygen uptake at Peak −4.0 ml.kg−1.min−1 ( −6.8 , −1.1 ) , p = 0.011 ; and post-exercise phosphocreatine recovery rate constant −0.34 min−1 ( −0.51 , −0.17 ) , p<0.001 . Conclusion The significant decrease in both whole-body physical fitness and in vivo muscle mitochondrial function raises the possibility that muscle mitochondrial mechanisms , no doubt multifactorial , may be important in deterioration of physical fitness following neoadjuvant chemoradiotherapy . This may have implication s for targeted interventions to improve physical fitness pre-surgery . Trial Registration Clinical trials.gov registration OBJECTIVE This study investigated the disparity between muscle metabolic rate and mitochondrial metabolism in human muscle of sedentary vs. active individuals . RESEARCH DESIGN AND METHODS Chronic activity level was characterized by a physical activity question naire and a triaxial accelerometer as well as a maximal oxygen uptake test . The ATP and O(2 ) fluxes and mitochondrial coupling ( ATP/O(2 ) or P/O ) in resting muscle as well as mitochondrial capacity ( ATP(max ) ) were determined in vivo in human vastus lateralis muscle using magnetic resonance and optical spectroscopy on 24 sedentary and seven active subjects . Muscle biopsies were analyzed for electron transport chain content ( using complex III as a representative marker ) and mitochondrial proteins associated with antioxidant protection . RESULTS Sedentary muscle had lower electron transport chain complex content ( 65 % of the active group ) in proportion to the reduction in ATP(max ) ( 0.69 ± 0.07 vs. 1.07 ± 0.06 mM sec(-1 ) ) as compared with active subjects . This lower ATP(max ) paired with an unchanged O(2 ) flux in resting muscle between groups result ed in a doubling of O(2 ) flux per ATP(max ) ( 3.3 ± 0.3 vs. 1.7 ± 0.2 μM O(2 ) per mM ATP ) that reflected mitochondrial uncoupling ( P/O = 1.41 ± 0.1 vs. 2.1 ± 0.3 ) and greater UCP3/complex III ( 6.0 ± 0.7 vs. 3.8 ± 0.3 ) in sedentary vs. active subjects . CONCLUSION A smaller mitochondrial pool serving the same O(2 ) flux result ed in elevated mitochondrial respiration in sedentary muscle . In addition , uncoupling contributed to this higher mitochondrial respiration . This finding resolves the paradox of stable muscle metabolism but greater mitochondrial respiration in muscle of inactive vs. active subjects
This analysis indicates that the current body of literature does not support a de facto decrease of in vivo muscle oxidative capacity in old age .
The heterogeneity of study results and identification of significant moderators provide clarity regarding apparent discrepancies in the literature , and indicate the importance of accounting for these variables when examining purported age-related differences in muscle oxidative capacity
Despite intensive efforts to underst and the extent to which skeletal muscle mitochondrial capacity changes in older humans , the answer to this important question remains unclear .
To determine what the preponderance of evidence from in vivo studies suggests , we conducted a systematic review and meta- analysis of the effects of age on muscle oxidative capacity as measured noninvasively by magnetic resonance spectroscopy .
A secondary aim was to examine potential moderators contributing to differences in results across studies , including muscle group , physical activity status , and sex .