Fatty acid-induced mitochondrial uncoupling in adipocytes as a key protective factor against insulin resistance and beta cell dysfunction : a new concept in the pathogenesis of obesity-associated type 2 diabetes mellitus Type 2 diabetes is associated with excessive food intake and a sedentary lifestyle . Local inflammation of white adipose tissue induces cytokine-mediated insulin resistance of adipocytes . This results in enhanced lipolysis within these cells . The fatty acids that are released into the cytosol can be removed by mitochondrial β-oxidation . The flux through this pathway is normally limited by the rate of ADP supply , which in turn is determined by the metabolic activity of the adipocyte . It is expected that the latter does not adapt to an increased rate of lipolysis . We propose that elevated fatty acid concentrations in the cytosol of adipocytes induce mitochondrial uncoupling and thereby allow mitochondria to remove much larger amounts of fatty acids . By this , release of fatty acids out of adipocytes into the circulation is prevented . When the rate of fatty acid release into the cytosol exceeds the β-oxidation capacity , cytosolic fatty acid concentrations increase and induce mitochondrial toxicity . This results in a decrease in β-oxidation capacity and the entry of fatty acids into the circulation . Unless these released fatty acids are removed by mitochondrial oxidation in active muscles , these fatty acids result in ectopic triacylglycerol deposits , induction of insulin resistance , beta cell damage and diabetes . Thiazolidinediones improve mitochondrial function within adipocytes and may in this way alleviate the burden imposed by the excessive fat accumulation associated with the metabolic syndrome . Thus , the number and activity of mitochondria within adipocytes contribute to the threshold at which fatty acids are released into the circulation , leading to insulin resistance and type 2 diabetes . Introduction Type 2 diabetes mellitus is generally associated with an enhanced energy intake and too little physical exercise . Also genetic factors determine the susceptibility to develop this disease . Whole-body insulin resistance and a state of low grade inflammation are early marker of the disease process -LSB- 1 -RSB- . Subsequently , hyperglycaemia develops due to an accelerated decline in beta cell function -LSB- 2 -- 4 -RSB- . Type 2 diabetes mellitus is often accompanied by other co-morbidities such as hypertension and dyslipidaemia . Together , they constitute the metabolic syndrome -LSB- 2 -RSB- . Here we present the concept that removal of fatty acids within white adipocytes by fatty acid-induced uncoupled mitochondrial β-oxidation protects the organism against fatty acid leakage out of adipocytes , thereby preventing fatty acid-induced insulin resistance in liver and muscle and lipotoxicity in pancreatic beta cells . A consequence of this concept is that mitochondrial dysfunction in adipocytes , either inherited or acquired , makes the organism more prone to develop insulin resistance and type 2 diabetes . Mitochondria and fatty acids One of the main functions of mitochondria , in addition to producing ATP , is to remove fatty acids by β-oxidation . In this way , mitochondria are able to remove NEFA and to protect the organism against fatty acid-induced insulin resistance and pancreatic beta cell lipotoxicity . β-Oxidation can take place in all cell types relevant for glucose homeostasis , including muscle , liver and adipocytes . During this process , fatty acids are oxidised in the mitochondrial matrix by NAD + and flavin adenine dinucleotide -LRB- FAD -RRB- , yielding acetyl coenzyme A , which is further degraded to CO2 by the citric acid cycle . The resulting NADH and FADH2 need to be recycled into NAD + and FAD by the respiratory chain so that additional fatty acid molecules can be oxidised . This requires a supply of ADP , which is converted into ATP by respiratory chain activity . The rate of conversion of ATP back into ADP , which is determined by the metabolic activity of the cell , determines the rate at which fatty acids can be removed by mitochondrial activity . If the capacity of the cell to oxidise fatty acids is to be enhanced , ATP needs to be reconverted into ADP at an increased rate . This occurs during exercise in contracting muscle . The resulting enhanced rate of ADP generation provides a major additional sink for the oxidation of fatty acids within the body . Only when mitochondria are in the uncoupled state can regeneration of NAD + and FAD occur without the conversion of ATP into ADP . The released energy is then converted into heat . Uncoupling is a physiological adaptation process , normally regulated by specific proteins -LSB- 5 -RSB- . It is remarkable that , like uncoupling proteins , fatty acids are capable of inducing mitochondrial uncoupling , especially when their concentrations exceed the binding capacity of fatty acid binding proteins -LSB- 6 -- 8 -RSB- . This implies that when unbound fatty acids are present in the cytosol of cells , mitochondria become less efficient at ATP production and generate more heat during the oxidation of NADH and FADH2 derived from food . Mitochondrial uncoupling in adipocytes by fatty acids may protect the organism against fatty acid-induced insulin resistance and lipotoxicity White adipocytes contain large amounts of mitochondria in their tiny cytosolic compartment -LSB- 9 , 10 -RSB- . There is no obvious reason why these cells need such a large capacity to produce ATP . We propose that , when uncoupled by fatty acids , these mitochondria prevent the release of fatty acids out of the adipocytes when the antilipolytic action of insulin is attenuated . Evidence is accumulating that inflammation of adipose tissue is an early step in the pathogenesis of type 2 diabetes . The combination of excessive food intake with a sedentary lifestyle results in the formation of large adipocytes overloaded with triacylglycerols . Through as yet unknown mechanisms the adipose tissue becomes inflamed and infiltrated by leucocytes . This leads to the release of inflammatory cytokines such as TNF-α -LSB- 11 -- 14 -RSB- , a potent inducer of insulin resistance in adipocytes which also induces lipolysis . As a result , fatty acids are released out of the large triacylglycerol pool -LSB- 15 -RSB- . We propose that , initially , a part of these fatty acids are removed inside adipocytes by partially uncoupled mitochondrial β-oxidation . In doing so , these mitochondria create a threshold for fatty acid release into the circulation , which would otherwise trigger the development of whole-body insulin resistance and pancreatic beta cell lipotoxicity , the latter expected to occur when the body can not utilise these released fatty acids as fuel , for example , in response to high food intake and little physical exercise . Our proposed mechanism is outlined in Fig. 1 . When low amounts of fatty acids are released out of the triacylglycerol pool in insulin-resistant adipocytes , these fatty acids can be removed by coupled β-oxidation . The rate of fatty acid removal by this pathway is determined by the rate of ADP regeneration within adipocytes , which is likely to be a more or less constant factor , merely determined by cellular metabolism and not affected by variations in the lipolytic rate . We propose that , when the rate of fatty acid release exceeds the rate of fatty acid removal by coupled β-oxidation , the increase in cytosolic concentrations of fatty acids not bound to binding proteins -LRB- unbound -RRB- induces a partial uncoupling of the mitochondria . Uncoupling by fatty acids has been shown in multiple in vitro experiments -LSB- 5 -- 8 , 16 -RSB- . Evidence of uncoupling in vivo is provided by a study in which exposure of heart muscle to fatty acids resulted in a decrease in ATP production and a concomitant increase in oxygen consumption -LSB- 17 -RSB- . When uncoupled , the mitochondria are able to remove much larger quantities of fatty acids through generation of heat . The degree of uncoupling increases in with further elevations in fatty acid concentration , thus generating more heat . This represents a dynamic adaptation of the efficiency of the mitochondrion , which is determined by the intracellular concentration of fatty acids . If , however , the rate of fatty acid release exceeds the maximum clearance rate , fatty acids may reach concentrations that are toxic to the mitochondrion -LSB- 18 -RSB- . At this point β-oxidation capacity collapses and fatty acids are released out of adipocytes and redistributed over other tissues in the body . These ectopic triacylglycerol deposits are associated with the development of insulin resistance in muscle and liver and lipotoxicity in pancreatic beta cells -LSB- 19 -RSB- . At this stage of the disease process physical exercise will , by virtue of the generation of large amounts of ADP in muscle tissue , protect against lipotoxicity and the development of insulin resistance . This is because the muscle switches to β-oxidation to regenerate ATP when fatty acids reach a concentration sufficient to make the muscle resistant to insulin-stimulated glucose uptake -LSB- 20 , 21 -RSB- . Fig. 1Consequences of fatty acid release from the adipocyte triacylglycerol pool . In insulin-sensitive adipocytes , fatty acid concentrations are kept low by insulin-induced antilipolytic action , re-esterification of fatty acids and mitochondrial β-oxidation . TNF-α induces insulin resistance and lipolysis . At low cytosolic concentrations of unbound fatty acids , the flux through mitochondrial β-oxidation is limited by the rate of ADP generation by cellular metabolism . At intermediate concentrations of unbound fatty acids , uncoupling of mitochondria is induced leading to continuous oxidation of fatty acids , independent of ADP supply . This process generates heat and keeps cytosolic fatty acid concentrations low . When the rate of fatty acid release from the triacylglycerol pool exceeds the rate of fatty acid removal , high cytosolic concentrations of unbound fatty acids develop , which induce mitochondrial damage -LSB- 18 -RSB- . This results in a decline in the capacity to remove fatty acids and the release of large amounts of fatty acids into the circulation . Unless these are removed by muscle activity they form ectopic triacylglycerol deposits and induce whole-body insulin resistance and beta cell damage . Dotted arrows indicate consequences ; continuous arrows , fluxes Discussion In our model for the development of obesity-induced whole-body insulin resistance and beta cell damage leading to type 2 diabetes , we propose a key role for fatty acid removal by adipose tissue mitochondria . The disease process , as outlined in Fig. 2 , is initiated by the development of cytokine-induced adipose tissue insulin resistance -LSB- 11 -- 15 -RSB- and results in the release of fatty acids into the cytosol of the adipocytes . Further increases in cytosolic fatty acids induce mitochondrial dysfunction -LSB- 18 -RSB- , decreasing the rate of β-oxidation , augmenting the fatty acid concentration , leading to their release into the circulation . These fatty acids are responsible for the development of insulin resistance in liver and muscle and lipotoxicity in pancreatic beta cells . Fatty acids do not appear to induce insulin resistance in adipocytes -LSB- 22 -RSB- , which otherwise would create a positive feedback loop whereby the release of fatty acids induces additional insulin resistance and further promotes the release of fatty acids . Fig. 2Proposed sequence of events leading to the development of hyperglycaemia during the metabolic syndrome . When adipocytes become overloaded with triacylglycerol , low-grade inflammation develops and inflammatory cytokines such as TNF-α induce insulin resistance in the adipocytes . This results in an elevated state of lipolysis . When fatty acids are inadequately removed within adipocytes because of mitochondrial dysfunction -LRB- for example , induced by fatty acids or HAART therapy , fatty acids appear in the circulation , where they induce insulin resistance of muscle and liver and malfunction of pancreatic beta cells . The elevated circulating fatty acid concentrations may also uncouple mitochondria in artery wall smooth muscle cells , thereby elevating the risk of hypertension -LSB- 46 -RSB- . Thiazolidinediones -LRB- TZDs -RRB- ameliorate the disease process in two ways : -LRB- 1 -RRB- by creating more mitochondria in adipose cells -LSB- 23 , 36 , 37 -RSB- , thereby enhancing the capacity for oxidation of fatty acids ; and -LRB- 2 -RRB- by enhanced re-esterification of fatty acids -LSB- 39 , 40 -RSB- Is there any evidence to support our model ? Several studies have shown that in adipose tissue from obese animal models and humans , mitochondrial -LRB- mt -RRB- DNA copy number and expression of mitochondrial genes is decreased -LSB- 23 , 24 -RSB- . In the diabetic state , mitochondrial β-oxidation of fatty acids was found to be attenuated . In addition , mitochondria showed an abnormal morphology -LSB- 24 -RSB- . These data support the concept of mitochondrial dysfunction in adipose tissue in states of obesity and type 2 diabetes . Furthermore , intake of high-fat food by healthy persons rapidly increases the basal metabolic rate . This increase is blunted in obese individuals , whereas obese individuals exhibit an increased thermogenesis . These observations are suggestive for a rapid effect of ingested fatty acids on thermogenesis by mitochondrial uncoupling . The data also suggest that , in obese individuals , mitochondria are already uncoupled or damaged and less responsive to further fatty acid-induced uncoupling -LSB- 25 -RSB- . In vitro studies have shown that fatty acid-induced uncoupling of the mitochondrial respiratory chain depends on the chemical nature of these fatty acids . Unsaturated fatty acids , such as oleic acid , are better uncouplers than saturated fatty acids -LSB- 8 -RSB- . This could imply that the inclusion of saturated fatty acids in the diet makes mitochondria less prone to uncoupling , resulting in the earlier release of fatty acids , i.e. at a lower fatty acid level . A further implication of our model is that a decline in mitochondrial function in adipocytes reduces the ability of these cells to store triacylglycerol . Inadvertently released fatty acids out of the triacylglycerol pool enter the circulation and are redistributed in other tissues . This occurs , for example , in individuals starting on highly active antiretroviral therapy -LRB- HAART -RRB- -LSB- 26 -- 29 -RSB- . The nucleoside analogues included in HAART inhibit mtDNA polymerase and induce a ∼ 30 -- 50 % reduction in mtDNA content in adipocytes and other tissues . HAART is associated with the redistribution of peripheral fat to the central and other compartments and with an elevated risk of developing the metabolic syndrome and type 2 diabetes . We see this clinical phenotype as a result of release of fatty acids by peripheral adipocytes , which in turn is due to a decrease in mitochondrial capacity to remove fatty acids . The fatty acids , after entering the circulation , induce insulin resistance and lipotoxicity to pancreatic beta cells and become stored as ectopic triacylglycerol deposits . Another example of a mitochondrial dysfunction is represented by patients carrying a 3243A > G mutation in mtDNA . This mutation results in an attenuated mitochondrial function . Most of these patients develop the maternally inherited diabetes and deafness -LRB- MIDD -RRB- syndrome . Remarkably , these patients usually have a BMI of < 25 kg/m2 . Furthermore , they exhibit ectopic triacylglycerol deposits in multiple tissues -LSB- 30 -- 33 -RSB- . This clinical picture suggests the attenuated storage of triacylglycerol in adipose tissue . Around mid-life , these patients show a decrease in insulin secretion , which may result from lipotoxicity to pancreatic beta cells . Congenital lipodystrophy is another clinical example showing that an inadequate storage of triacylglycerol in adipocytes contributes to ectopic triacylglycerol deposits and the development of severe whole-body insulin resistance and diabetes -LSB- 34 -RSB- . In contrast , improved mitochondrial function specifically in adipocytes is seen in individuals taking thiazolidinediones . These drugs are widely used to ameliorate whole-body insulin resistance in patients suffering from type 2 diabetes mellitus and the metabolic syndrome . These drugs bind to peroxisome proliferator-activated receptor-γ receptors which are highly expressed in adipocytes and in cells from the immune system , but low in liver and muscle -LSB- 35 -RSB- . These drugs increase mitochondrial copy number and mitochondrial gene expression specifically in adipose tissue -LSB- 23 , 36 , 37 -RSB- . Clinically , these drugs improve storage of triacylglycerol in peripheral adipocytes and ameliorate fatty acid-related insulin resistance . Patients taking these drugs tend to store more triacylglycerol in their adipocytes , leading to weight gain -LSB- 38 -RSB- . Together , these clinical data suggest that correct mitochondrial function is needed for adequate storage of fatty acids as triacylglycerol in adipocytes . By this means the organism is protected against the fatty acid-induced development of insulin resistance and lipotoxicity to the pancreas . As thiazolidinediones also induce the expression of genes involved in the neogenesis of glycerol , these drugs also enhance the re-esterification of fatty acids -LSB- 36 , 39 , 40 -RSB- . This also contributes to the removal of fatty acids from the circulation and protects adipocyte mitochondria against fatty acid-induced damage . Because part of the glycerol in adipocytes is synthesised through pathways that are dependent upon mitochondrial function -LSB- 36 -RSB- , this suggests that changes in mitochondrial function also may affect the rate of glycerol production and thereby the rate of fatty acid esterification . To be able to perform , uncoupled β-oxidation mitochondria require the presence of sufficient amounts of oxygen . It has been suggested that a state of hypoxia occurs in expanding adipose tissue during the development of obesity and that this state may contribute to the development of the metabolic syndrome -LSB- 41 , 42 -RSB- . Our model predicts that hypoxia in adipocytes would lead to a reduced rate of fatty acid removal inside these cells and to more fatty acid release into the circulation . The sensitivity of an individual to the development of type 2 diabetes as a result of lifestyle is determined by genetic factors . Multiple genetic variants that modulate the risk of an individual for the development of diabetes have been identified , including genetic variants related to mitochondrial function . A high penetrance mutation in mtDNA has been found to be associated with the MIDD syndrome . This mutation predominantly affects the activity of complex I of the respiratory chain -LSB- 43 -RSB- . In the same biochemical pathway a mutation in the LARS2 gene , which encodes mitochondrial leucyl-tRNA synthetase 2 , also modulates the risk for diabetes -LSB- 44 -RSB- . Furthermore , genetically determined changes in expression levels of components of the mitochondrial respiratory chain have been found to be associated with an increased risk of developing type 2 diabetes mellitus -LSB- 45 -RSB- . These genetic factors are likely to result in a decreased capacity of the mitochondria to remove fatty acids through uncoupled β-oxidation . Thereby , a genetic predisposition can lower the threshold for fatty acid release by adipocytes into the circulation and as a result enhance the risk for type 2 diabetes . Our model of the pathogenesis of type 2 diabetes mellitus requires experimental verification of several points , and it certainly does not exclude the involvement of additional factors such as the coregulation of whole-body insulin action and insulin secretion through adipokines and the involvement of uncoupling proteins in setting the threshold for fatty acid-induced uncoupling of mitochondria . However , we see the way fatty acids interact with mitochondria in the cytosol of adipocytes as a major initiating event in the disease process leading to the metabolic syndrome and type 2 diabetes mellitus .

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O O O B I O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O B I O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O B O O O O B I O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O B I O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O B O O B I O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O B O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O B I O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O B O O B I O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B I O O B O O O O B O O O O O O O O O O O O O O O B I I I O

adipocytes
fatty acids
haart
mitochondria
type 2 diabetes mellitus


Health-related physical fitness of adolescents and young adults with myelomeningocele To assess components of health-related physical fitness in adolescents and young adults with myelomeningocele -LRB- MMC -RRB- , and to study relations between aerobic capacity and other health-related physical fitness components . This cross-sectional study included 50 adolescents and young adults with MMC , aged 16 -- 30 years -LRB- 25 males -RRB- . Aerobic capacity was quantified by measuring peak oxygen uptake -LRB- peakVO2 -RRB- during a maximal exercise test on a cycle or arm ergometer depending on the main mode of ambulation . Muscle strength of upper and lower extremity muscles was assessed using a hand-held dynamometer . Regarding flexibility , we assessed mobility of hip , knee and ankle joints . Body composition was assessed by measuring thickness of four skin-folds . Relations were studied using linear regression analyses . Average peakVO2 was 1.48 ± 0.52 l/min , 61 % of the participants had subnormal muscle strength , 61 % had mobility restrictions in at least one joint and average sum of four skin-folds was 74.8 ± 38.8 mm . PeakVO2 was significantly related to gender , ambulatory status and muscle strength , explaining 55 % of its variance . Adolescents and young adults with MMC have poor health-related physical fitness . Gender and ambulatory status are important determinants of peakVO2 . In addition , we found a small , but significant relationship between peakVO2 and muscle strength . Introduction During the last decades , life expectancy of persons with myelomeningocele -LRB- MMC -RRB- has increased and many will nowadays survive into adulthood -LRB- Bowman et al. 2001 -RRB- . As a consequence , lifestyle-related diseases , such as cardiovascular disease and diabetes mellitus , will be of increasing concern in this patient group . Therefore , more attention towards a healthy lifestyle is warranted . Similar to the general population , persons with MMC develop their own lifestyle during the transition from adolescence to adulthood . At this age , special attention should be paid to optimize the lifestyle in order to improve health throughout life . Physical fitness is recognized as an important component of health -LRB- Lamb et al. 1988 ; Twisk et al. 2002 -RRB- and it may be important for the performance of functional activities and quality of life -LRB- Noreau and Shephard 1995 ; Stewart et al. 1994 -RRB- . Low physical fitness may result in high physical strain during the performance of activities -LRB- Bruinings et al. 2007 -RRB- . As a consequence , activity levels may decrease due to fatigue and discomfort , exacerbating low physical fitness . Caspersen and co-workers defined several health-related components of physical fitness , i.e. aerobic capacity , muscle strength and endurance , flexibility and body composition -LRB- Caspersen et al. 1985 -RRB- . Only a few studies are available on health-related physical fitness in persons with MMC . In a previous study in adolescents and young adults with MMC , we found that average peak oxygen uptake -LRB- peakVO2 -RRB- was 42 % lower than normative values of healthy peers , with lower values in non-ambulatory than in ambulatory persons -LRB- Buffart et al. in press -RRB- . Several other studies have also reported low aerobic capacity -LRB- Agre et al. 1987 ; Sherman et al. 1997 ; van den Berg-Emons et al. 2003 -RRB- . Furthermore , children with MMC , and particularly non-ambulatory children , were found to have reduced strength of lower extremity muscles -LRB- Agre et al. 1987 ; McDonald et al. 1991 ; Schoenmakers et al. 2004 -RRB- . Hip and knee contractures have been reported in respectively 18 % and 36 % of adolescents and young adults with MMC and hydrocephalus -LRB- Verhoef et al. 2004 -RRB- . Finally , high levels of body fat have been found in persons with MMC -LRB- Bandini et al. 1991 ; Mita et al. 1993 ; Shepherd et al. 1991 -RRB- ; previously we reported that 35 % of adolescents and young adults with MMC were obese -LRB- Buffart et al. in press -RRB- . Because these previous studies lack simultaneous assessment of several health-related physical fitness components , the relation between aerobic capacity and other components remains unclear . Insight in these inter-relations may show for example , whether focusing on peripheral factors such as muscle strength would have additional value for improving aerobic capacity . Due to the scarcity of studies in persons with MMC , the first aim of this study was to describe health-related physical fitness i.e. aerobic capacity , muscle strength , joint flexibility and body composition in a relatively large group of adolescents and young adults with MMC , allowing descriptions of subgroups regarding gender and ambulatory status . Secondly , we wanted to study the relation between aerobic capacity and other components of health-related physical fitness , controlled for relevant personal and disease-related characteristics . Studies in persons with other chronic conditions such as spinal cord injury have shown relations between aerobic capacity and muscle strength -LRB- Haisma et al. 2006 ; Janssen et al. 1993 ; Zoeller et al. 2005 -RRB- . Therefore , also in persons with MMC , we expected aerobic capacity to be related to muscle strength . Method Participants Recruitment Adolescents and young adults with MMC , aged between 16 and 30 years , were recruited from the university hospitals in Rotterdam , Leiden , Utrecht and Amsterdam and all rehabilitation centers in the Southwest of the Netherlands . Exclusion criteria were complete dependence on an electric wheelchair , presence of disorders other than MMC that affect daily physical activity -LRB- e.g. rheumatoid arthritis -RRB- , and presence of disorders that contra-indicate a maximal exercise test -LRB- e.g. exercise-induced ischemia or arrhythmias , uncontrolled hypertension and exercise limitation due to chronic obstructive pulmonary disease -RRB- . We invited 171 persons of whom 50 participated in the study -LRB- 29 % -RRB- . Main reasons for non-participation were no interest , lack of time or duration of the measurements . No differences were found between participants and non-participants regarding age , gender , level of lesion and presence of hydrocephalus , as measured with an independent t-test or Chi square test -LRB- Buffart et al. in press -RRB- . All participants and parents of adolescents aged less than 18 years gave written informed consent before participating in the study . The Medical Ethics Committee of the Erasmus MC Rotterdam and of all participating institutes approved the study . Characteristics In total , 25 males and 25 females -LRB- mean age 21.2 ± 4.5 years -RRB- participated in the study . Table 1 presents personal and disease-related characteristics of participants . Neurological level of lesion and the presence of hydrocephalus were obtained from the medical records . Five categories of neurological level were distinguished : thoracic , thoracolumbar , lumbar , lumbosacral and sacral . We considered hydrocephalus to be present when a shunt was placed . Ambulatory status was determined according to the classification of Hoffer and co-workers -LRB- Hoffer et al. 1973 -RRB- : -LRB- 1 -RRB- community ambulator , walking indoors and outdoors , -LRB- 2 -RRB- household ambulator , walking only indoors , and -LRB- 3 -RRB- non -LRB- functional -RRB- ambulator . Non-functional ambulators walk only during therapy sessions and non-ambulators are completely wheelchair dependent . Since main mode of ambulation in daily life is similar between non-functional ambulators and non-ambulators , we combined these two groups . Educational level was categorized as low -LRB- pre-vocational practical education or lower level -RRB- , medium -LRB- pre-vocational theoretical education and secondary education -RRB- or high -LRB- higher education and university -RRB- -LRB- Donkervoort et al. 2007 -RRB- . Table 1Personal and disease-related characteristics of participants -LRB- n = 50 -RRB- Gender -LRB- % male -RRB- 50Age -LRB- mean ± SD in years -RRB- 21.2 ± 4.5 Height -LRB- mean ± SD in m -RRB- 1.57 ± 0.12 Body mass -LRB- mean ± SD in kg -RRB- 67.6 ± 15.6 Level of lesion -LRB- % -RRB- Thoracic2 Thoracolumbar14 Lumbar28 Lumbosacral42 Sacral14 Hydrocephalus -LRB- % -RRB- 82Ambulatory status -LRB- % -RRB- a Community ambulator30 Household ambulator14 Non -LRB- functional -RRB- ambulator56Educational level -LRB- % -RRB- Low37 Medium39 High24aNo gender differences as tested with a Chi square test Aerobic capacity Aerobic capacity was measured in a progressive maximal exercise test , based on the McMaster All-Out Progressive Continuous Cycling and Arm test -LRB- Bar-Or 1983 -RRB- , on an electronically braked arm or cycle ergometer -LRB- Jaeger ER800SH and ER800 respectively ; Jaeger Toennies , Breda , The Netherlands -RRB- . Studying patients with cerebral palsy who were partly wheelchair-dependent , Bhambani and co-workers concluded that maximal exercise testing during the main mode of ambulation elicits the highest oxygen uptake -LRB- Bhambhani et al. 1992 -RRB- . Therefore , depending on their main mode of ambulation , participants performed an arm crank test -LRB- n = 33 -RRB- while sitting in their own immobilized wheelchair with cranks at shoulder height , or a leg cycle exercise test -LRB- n = 17 -RRB- . The test was preceded by a 3-minute warm-up -LRB- 5 W for arm ergometry and 20 W for cycle ergometry -RRB- , followed by a resting period of 5 min . During the test , resistance was increased every 2 min with a variable load , ensuring that total individual exercise duration ranged from 8 to 12 min . The pedal/crank rate was 60 rpm and strong verbal encouragement was given throughout the test . The test was terminated when the subject stopped due to exhaustion . Gas exchange was determined continuously using a breath-by-breath portable measurement system -LRB- K4b2 , COSMED , Rome , Italy -RRB- . Calibration was performed before each test with reference gases . Heart rate was measured continuously using a heart rate -LRB- HR -RRB- monitor which was attached to the system , and participants were fitted with a transmitter belt around the chest -LRB- Polar Electro , Finland -RRB- . Aerobic capacity was defined as the mean oxygen uptake during the last 30 s of exercise -LRB- peakVO2 , in l/min -RRB- . In addition , for those measured during cycle ergometry , values of aerobic capacity were expressed as percentage of reference values of Dutch able-bodied sedentary males and females of similar ages , as estimated from a submaximal exercise test on a cycle ergometer using the nomogram of Åstrand -LRB- Vos 2001 -RRB- . Peak work load -LRB- peakW -RRB- was defined as the highest work load maintained for at least 1 min . In addition , the ventilatory anaerobic threshold -LRB- VAT -RRB- was estimated by the ventilatory equivalent method , when the ventilatory equivalent for O2 -LRB- Ve/VO2 -RRB- and the end-tidal O2 partial pressure -LRB- petO2 -RRB- increased while ventilatory equivalent for CO2 -LRB- Ve/VCO2 -RRB- and end-tidal CO2 partial pressure -LRB- petCO2 -RRB- remained stable -LRB- Reinhard et al. 1979 ; Wassermann et al. 1999 -RRB- . VAT was also expressed relative to the measured peakVO2 -LRB- VAT % -RRB- . HR and respiratory exchange ratio -LRB- RER -RRB- were used as objective criteria for maximal exercise . Subjective strain was measured at the end of the final stage using the modified Borg scale of rating perceived exertion -LRB- RPE -RRB- , which is a vertical scale labelled from 0 -LRB- no effort at all -RRB- to 10 -LRB- maximal effort -RRB- -LRB- Borg 1982 ; Mahler et al. 1987 -RRB- . Muscle strength We measured strength of two large muscle groups of the lower and upper extremity with a hand-held dynamometer -LRB- MicroFet , Hoggan Health Industries -RRB- using the `` break '' testing method . We measured strength of hip flexors and knee extensors in persons whose main mode of ambulation was walking . In persons whose main mode of ambulation was wheelchair-driving , we measured strength of shoulder abductors and elbow extensors . The positions and the performance of the measurements were according to van der Ploeg and co-workers -LRB- van der Ploeg et al. 1991 -RRB- . The applicator of the dynamometer was held against the distal part of the limb segment , and participants were asked to build up their force to a maximum against it . The examiner applied sufficient resistance just to overcome the force exerted by the participant , and the applicator was then immediately moved away from the limb segment and the measured force was recorded . Each trial lasted approximately 4 s , and three repetitions were performed with 1 min rest in between . We used the average value of three repetitions of the dominant side for further analyses because we found no differences between the dominant and non-dominant side -LRB- tested with a paired samples t-test -RRB- . To assess whether muscle strength was subnormal and to be able to compare strength of upper and lower extremity muscles , values were normalized to Z-scores using reference values of healthy males and females . For hip flexors , shoulder abductors and elbow extensors we used reference values of Phillips and co-workers for males and females aged 20 -- 29 years -LRB- Phillips et al. 2000 -RRB- and for knee extensors , we used reference values of Bohannon and co-workers -LRB- Bohannon 1997 -RRB- . In case the examiner could not resist the muscle strength , Z-score was set at 2 . We used the lowest Z-score of the upper or lower extremity as indicator of muscle strength , and we considered muscle weakness to be present when Z-score ≤ − 2 . Flexibility As indicator of flexibility of lower extremity we assessed passive mobility of hip and knee joint while participants were lying supine and of the ankle joint while they were sitting . We considered mobility to be restricted when extension of hip and knee joint and ankle dorsal flexion did not reach neutral position . Since no differences were found in mobility restrictions between dominant and non-dominant side -LRB- tested with the Wilcoxon signed rank test -RRB- we used the results of the dominant side to calculate a sum score of joint mobility ranging from 0 -LRB- no mobility restrictions in any joint -RRB- to 3 -LRB- all three joints have mobility restrictions -RRB- . Body composition Height was measured with a flexible tape while lying on a bed . In case of joint contractures , measurements were performed from joint to joint . Body mass of ambulatory persons was obtained while standing on a Seca scale and of non-ambulatory persons while sitting on an electronic scale -LRB- Cormier , France -RRB- . Thickness of four skin-folds -LRB- biceps , triceps , subscapular , and suprailiac -RRB- was measured twice on the right side of the body with a Harpenden caliper -LRB- Burgess Hill , UK -RRB- and mean values were used for further analyses . In addition , sum of four skin-folds were expressed as percentage of reference values of Dutch sedentary males and females of similar ages -LRB- Vos 2001 -RRB- . Statistical analysis Results of health-related fitness components are presented as mean ± standard deviation -LRB- SD -RRB- for the total group and for subgroups regarding gender and ambulatory status . Simple linear regression analyses were used to study relations between personal and disease-related characteristics and peakVO2 -LRB- in l/min -RRB- , in order to detect relevant determinants to include in the multiple regression models . Multiple linear regression analyses for peakVO2 were carried out in two steps . First , we built a model including relevant personal and disease-related characteristics . In the second step , we studied whether other health-related physical fitness components , i.e. muscle strength -LRB- Z-score -RRB- , sum of four skin-folds -LRB- mm -RRB- , and joint mobility -LRB- number of restricted joint -RRB- , were significantly related to peakVO2 , controlling for the personal and disease-related characteristics from step 1 . We presented the standardized regression coefficients -LRB- β -RRB- and explained variance -LRB- R2 -RRB- of the linear regression models . Statistical analyses were performed using SPSS 12.0 for Windows . P ≤ 0.05 were considered significant . In the analyses , we pooled the data of peakVO2 measured during arm and cycle ergometry , and corrected for differences in exercise mode . Due to high collinearity between type of ergometer and ambulatory status -LRB- correlation coefficient -LRB- r -RRB- = 0.92 , P < 0.001 -RRB- , we adjusted the analyses for ambulatory status as proxy for type of ergometer , because clinically , ambulatory status would be more meaningful . Furthermore , due to overlap between lesion level and ambulatory status -LRB- r = 0.58 ; P < 80.001 -RRB- , we chose to only correct for ambulatory status in the multiple regression analyses . Ambulatory status was determined during the study , whereas level of lesion was obtained from medical records . The national study on adolescents with spina bifida in the Netherlands -LRB- ASPINE -RRB- reported that the level of lesion as mentioned in medical records may be unreliable because lesions are determined at different ages , sometimes using the motor level and sometimes using the sensory level , and often lacking descriptions of methods -LRB- Verhoef et al. 2004 -RRB- . Results Descriptive results of aerobic capacity , muscle strength , joint mobility and body composition for the total group and for subgroups regarding gender and ambulatory status are presented in Table 2 . Average peakVO2 was 1.48 ± 0.52 l/min . For persons measured during cycle ergometry -LRB- n = 17 -RRB- , peakVO2 corresponded to 67 ± 15 % of reference values . Sixty-one percent of the participants had subnormal muscle strength as indicated by Z-scores and 61 % had mobility restrictions in one or more joints . Average sum of four skin-folds was 74.8 ± 38.8 mm , corresponding to 159 ± 77 % of normative values -LRB- Table 2 -RRB- . According to objective and subjective criteria most participants reached their peak exercise performance . Average peakHR was 174 ± 19 beats per minute , which was 90.4 ± 9.6 % of the age predicted maximum -LRB- 220 -- age for cycle ergometry ; 210 -- age for arm ergometry -RRB- and average peakRER was 1.17 ± 0.22 . Average RPE was 6.2 ± 2.2 , indicating that participants experienced the exercise as heavy to very heavy . Table 2Descriptive results of health-related physical fitness components for the total group and for subgroups regarding gender and ambulatory statusAll -LRB- n = 50 -RRB- GenderAmbulatory statusMale -LRB- n = 25 -RRB- Female -LRB- n = 25 -RRB- Community -LRB- n = 15 -RRB- Household -LRB- n = 7 -RRB- Non -LRB- functional -RRB- -LRB- n = 28 -RRB- Aerobic capacity -LRB- mean ± SD -RRB- PeakVO2 -LRB- l/min -RRB- 1.48 ± 0.521.78 ± 0.511.18 ± 0.301.85 ± 0.571.44 ± 0.451.29 ± 0.40 % of reference valuesa67 ± 1571 ± 1361 ± 1868 ± 1654 ± 2 -- PeakVO2 -LRB- ml/kg min -RRB- 22.6 ± 8.228.1 ± 7.017.0 ± 4.729.0 ± 7.722.3 ± 6.619.2 ± 6.8 Peak oxygen pulse -LRB- ml/bpm -RRB- 8.7 ± 3.010.1 ± 2.87.3 ± 2.410.7 ± 2.87.8 ± 2.47.8 ± 2.8 PeakRER1 .17 ± 0.221.17 ± 2.281.18 ± 0.201.15 ± 0.221.27 ± 0.161.16 ± 0.24 PeakW -LRB- W -RRB- 91 ± 42113 ± 4369 ± 28123 ± 4297 ± 3573 ± 34PeakHR -LRB- bpm -RRB- 174 ± 19179 ± 16169 ± 20173 ± 21183 ± 14172 ± 18PeakHR % of predicted maximum90 ± 1092 ± 889 ± 1087 ± 1095 ± 891 ± 10VAT -LRB- l/min -RRB- 1.20 ± 0.431.39 ± 0.441.01 ± 0.321.55 ± 0.451.07 ± 0.291.05 ± 0.34 VAT % 82 ± 1580 ± 1486 ± 1684 ± 1077 ± 2283 ± 16Muscle strength -LRB- mean ± SD -RRB- Z-score − 2.1 ± 1.8 − 2.3 ± 2.1 − 1.9 ± 1.5 − 2.7 ± 2.2 − 2.0 ± 1.6 − 1.8 ± 1.7 Weak strength : Z-score ≤ − 2 -LRB- % -RRB- 615864795754Joint mobility -LRB- median -LSB- range -RSB- -RRB- Number of restricted joints 1 -LSB- 0 -- 3 -RSB- 1 -LSB- 0 -- 3 -RSB- 1 -LSB- 0 -- 3 -RSB- 0 -LSB- 0 -- 2 -RSB- 1 -LSB- 0 -- 2 -RSB- 1.5 -LSB- 0 -- 3 -RSB- Impaired mobility in any joint -LRB- % -RRB- 615467295782Body composition -LRB- mean ± SD -RRB- Sum of four skin-folds -LRB- mm -RRB- 74.8 ± 38.851.2 ± 24.6100.4 ± 35.159.1 ± 29.266.5 ± 34.786.0 ± 42.0 % of reference values159 ± 77146 ± 79173 ± 73121 ± 52160 ± 101181 ± 75aOnly for those measured on the cycle ergometer , n = 17 -LRB- ten males , seven females -RRB- Several personal and disease-related characteristics were related to peakVO2 -LRB- Table 3 -RRB- . PeakVO2 was higher in males than in females -LRB- β = − 0.61 ; P < 0.001 -RRB- , higher in community ambulatory persons than in household and non-ambulatory persons -LRB- β = − 0.48 ; P < 0.001 -RRB- and higher in persons with a lower level of lesion -LRB- β = − 0.43 ; P = 0.002 -RRB- . Age , presence of hydrocephalus and educational level were not related to peakVO2 . Table 3Regression models for aerobic capacityIndependent variablesAerobic capacity -LRB- peakVO2 , in l/min -RRB- β P-valueR2Simple regression analysis Personal characteristics Gender − 0.61 < 0.0010.36 Age − 0.07 0.65 -- Lesion level − 0.430.0020.17 Hydrocephalus − 0.18 0.22 -- Ambulatory status − 0.48 < 0.0010.22 Educational level0 .130.39 -- Multiple regression analysis Step 1a Personal characteristics0 .50 Gender − 0.55 < 0.001 Ambulatory status − 0.40 < 0.001 Step 2b Inter-relations Muscle strength -LRB- Z-score -RRB- 0.220.040.55 Body composition -LRB- sum of four skin-folds in mm -RRB- 0.250.080.53 Joint mobility -LRB- number of restricted joints -RRB- 0.000.98 -- Significant betas are presented in boldβ standardized regression coefficient , R2 explained variance , Gender male -LRB- 0 -RRB- , female -LRB- 1 -RRB- , Lesion level sacral -LRB- 1 -RRB- , lumbosacral -LRB- 2 -RRB- , lumbar -LRB- 3 -RRB- , thoracolumbar -LRB- 4 -RRB- , thoracic -LRB- 5 -RRB- , Hydrocephalus no -LRB- 0 -RRB- , yes -LRB- 1 -RRB- , Ambulatory status community ambulator -LRB- 1 -RRB- , household ambulator -LRB- 2 -RRB- , non -LRB- functional -RRB- ambulator -LRB- 3 -RRB- , Educational level : low -LRB- 0 -RRB- , medium -LRB- 1 -RRB- , high -LRB- 2 -RRB- aDue to large overlap between ambulatory status and lesion level , we only included ambulatory statusbRelations between aerobic capacity and other fitness components controlled for gender and ambulatory status Fifty percent of the variance in peakVO2 was explained by gender and ambulatory status -LRB- Table 3 -RRB- . In addition , when controlling for both variables , we found that participants with higher muscle strength had higher values of peakVO2 -LRB- β = 0.22 ; P = 0.04 -RRB- explaining an additional 5 % of the variance in peakVO2 . Furthermore , we found that participants with higher sum of four skin-folds tended to have higher values of peakVO2 -LRB- β = 0.25 ; P = 0.08 -RRB- . Discussion Components of health-related physical fitness In the present study , several health-related components of physical fitness were studied simultaneously in a relatively large group of adolescents and young adults with MMC . In general , most participants had poor health-related physical fitness . Compared to the general population and compared to other patient groups , persons with MMC had low aerobic capacity . Regarding community ambulatory persons with MMC , values of peakVO2 were 32 % lower than the reference values for able-bodied people and 23 % lower than the average peakVO2 of males with spastic diplegia measured during cycle ergometry -LRB- Lundberg 1978 -RRB- . However , peakVO2 is influenced by the amount of active muscle mass -LRB- Davies and Sargeant 1974,1975 ; Lewis et al. 1983 -RRB- , which may possibly be reduced due to paresis of lower extremity muscles . PeakVO2 in non-ambulatory persons with MMC was lower than in ambulatory persons which may be caused by the lower amount of active muscle mass during arm ergometry compared to cycling . In able-bodied people , arm exercise induces a peakVO2 ranging from 53 to 73 % of that achieved with lower extremity exercise -LRB- Bar-Or and Zwiren 1975 -RRB- . If that ratio is also applicable to non-ambulatory persons who may be accustomed to using their arm and shoulder muscles , adapted values of average peakVO2 would range between 1.76 and 2.43 l/min , which is of comparable range to the peakVO2 in ambulatory persons with MMC . Furthermore , compared to males with spinal cord injuries with lesions below T10 measured during arm ergometry -LRB- Janssen et al. 2002 -RRB- , the peakVO2 in non -LRB- functional -RRB- - ambulatory males with MMC was 22 % lower . We therefore assumed that the poor aerobic capacity we found in persons with MMC may be influenced by reduced active muscle mass , but also deconditioning is likely to be present . This is supported by previous studies showing that adolescents and young adults with MMC were inactive , and that inactivity was associated with lower aerobic capacity -LRB- van den Berg-Emons et al. 2001 -RRB- , particularly in non-ambulatory persons with MMC -LRB- Buffart et al. in press -RRB- . VAT is another indicator of aerobic capacity , which was strongly correlated to peakVO2 in the present study sample -LRB- r = 0.84 ; P < 0.001 -RRB- . In the general population , VAT roughly corresponds to 50 -- 60 % of VO2max during leg exercise -LRB- Davis et al. 1997 -RRB- , and values of 40 -- 60 % have been found in the able-bodied population during arm exercise -LRB- Flandrois et al. 1986 ; Lin et al. 1993 ; Schneider et al. 1999 -RRB- . Paradoxically , we found VAT to be at 82 % of peakVO2 suggesting high aerobic capacity . Comparably , Coutts and McKenzie found that persons with tetraplegia had lower VAT than persons with paraplegia caused by smaller muscle mass , but they had higher VAT % , and it was suggested that values of peakVO2 were low in relation to VAT -LRB- Coutts and McKenzie 1995 -RRB- . Fifty-four percent of the non-ambulators and 79 % of the community ambulators had subnormal strength in at least one of the major muscle groups . The relatively better performance of non-ambulators compared to ambulators in this respect might be explained by their relatively higher muscle strength in the upper extremities due to the habituation of using their arms for wheelchair propulsion . Furthermore , in contrast to lower extremity muscles , the neurological level of lesion will not disturb innervations of upper extremity muscles , which suggests that the weak upper extremity strength we found in non-ambulators is due to atrophy of muscles as a consequence of disuse . Weak strength of lower extremity muscles in ambulatory persons with MMC corresponds to previous findings in children with MMC -LRB- Agre et al. 1987 ; McDonald et al. 1991 ; Schoenmakers et al. 2004 -RRB- and might be related to disturbed innervations as well as to disuse of muscles . Results of the present study support the findings of Verhoef and co-workers that a large proportion of persons with MMC have reduced joint mobility -LRB- Verhoef et al. 2004 -RRB- . Similar to the results of Agre and co-workers restrictions in joint mobility in the lower extremities were mainly present in non-ambulatory persons with MMC -LRB- Agre et al. 1987 -RRB- . We found high sum of four skin-folds , particularly in females and non-ambulatory , which is in agreement with high levels of body fat reported in previous studies -LRB- Bandini et al. 1991 ; Mita et al. 1993 ; Shepherd et al. 1991 -RRB- . Relations between aerobic capacity and other components of health-related physical fitness The results of the regression analyses indicated muscle strength was associated to peakVO2 when controlling for gender and ambulatory status . This finding is in accordance with literature on persons with spinal cord injury -LRB- Haisma et al. 2006 ; Janssen et al. 1993 ; Zoeller et al. 2005 -RRB- . In contrast to gender and ambulatory status , muscle strength is modifiable . Strength training may increase muscle mass and thus metabolizing mass contributing to higher peakVO2 -LRB- Janssen et al. 1993 -RRB- . In persons with spinal cord injury , strength training resulted in increased peakVO2 -LRB- Cooney and Walker 1986 -RRB- . Because causality can not be established with the cross-sectional design of the present study , future studies should confirm whether strength training results in increased aerobic capacity in persons with MMC . However , considering the small , but significant , contribution of muscle strength to the explained variance , we assume this specific effect to be small . In this respect , it seems that mainly aerobic training is needed in order to improve aerobic capacity ; however , including strength training may have additional value . Body composition tended to be positively related to aerobic capacity , indicating that persons with more body fat had higher values of peakVO2 . This relation may be caused by the greater fat-free mass of overweight persons concomitant with a greater body size -LRB- Unnithan et al. 2006 -RRB- . Joint mobility was not related to aerobic capacity . However , in non-ambulators we might have underestimated the relation because we did not measure mobility of upper extremity joints . Nevertheless , good flexibility of lower extremity is suggested to be important to prevent problems later in life , such as problems with personal hygiene and transfer capabilities -LRB- Agre et al. 1987 -RRB- . Limitations of the study The methodology of the study had some limitations . First , because it is suggested that the primary mode of ambulation elicits the highest values of peakVO2 -LRB- Bhambhani et al. 1992 -RRB- , we used different exercise modes to assess aerobic capacity for ambulatory and non-ambulatory persons . However , due to large differences in active muscle mass , arm and leg exercise have different physiological responses . Therefore , we corrected for ambulatory status as proxy measure for type of ergometer when analysing relations between aerobic capacity and the other health-related fitness components . Furthermore , because the main mode of ambulation of ambulatory persons is walking rather than cycling , we may have underestimated peakVO2 in some ambulatory persons with MMC who rarely cycle . However , in clinical practice , the cycle ergometer seems to be more practical because physically disabled people may experience severe balance problems on the treadmill , and on the cycle it is possible to strap the feet to the pedals -LRB- Lundberg 1978 -RRB- . Peripheral local fatigue may have caused exercise cessation before reaching maximum oxygen uptake , however , based on the objective -LRB- peakHR and peakRER -RRB- and subjective criteria of maximal exercise -LRB- RPE -RRB- , it may be concluded that values of peakVO2 are reasonable . Furthermore , muscle strength was measured using hand-held dynamometry . This method is known to be cheap , quickly applicable -LRB- van der Ploeg et al. 1984 -RRB- and reliable -LRB- Bohannon 1997 -RRB- . However , for an average examiner , values above 250 N are considered too high to apply sufficient resistance -LRB- van der Ploeg et al. 1991 -RRB- , which may lead to less accurate results in strong muscle groups . Using absolute values of strength measured with an isokinetic device , instead of expressing muscle strength as Z-score , might provide more detailed insight into the relation between strength peakVO2 . However , the current measurement method and use of Z-scores are considered adequate to determine weakness of major muscle groups . Finally , the response rate was low , which hampers generalization of results . However , personal and disease-related characteristics did not differ between participants and non-participants . Moreover , the prevalence of middle-level -LRB- lumbosacral -RRB- and high-level -LRB- lumbar or thoracolumbar -RRB- lesions of the present study sample was comparable to the persons who participated in the national ASPINE study -LRB- Verhoef et al. 2004 -RRB- . Despite , a selection bias may have occurred since it could be that the more active and more fit people had higher interest in participating than the less active and less fit ones , which may have led to an overestimation of health-related physical fitness components . In conclusion , the results of the present study show that both ambulatory and non-ambulatory adolescents and young adults with MMC have poor health-related physical fitness . A large part of the variance in aerobic capacity is explained by gender and ambulatory status . Results showed a small but significant relationship between peakVO2 and muscle strength , suggesting that adding strength training to aerobic training may have additional value in increasing peakVO2 .

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I O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O

spina bifida
aerobic capacity
muscle strength
joint mobility
body fat