L.J.C. van Loon

Dietary Protein Digestion and Absorption Rates and the Subsequent Postprandial Muscle Protein Synthetic Response Do Not Differ between Young and Elderly Men

Impaired digestion and/or absorption of dietary protein lowers postprandial plasma amino acid availability and, as such, could reduce the postprandial muscle protein synthetic response in the elderly. We aimed to compare in vivo dietary protein digestion and absorption and the subsequent postprandial muscle protein synthetic response between young and elderly men. Ten elderly (64 +/- 1 y) and 10 young (23 +/- 1 y) healthy males consumed a single bolus of 35 g specifically produced, intrinsically l-[1-(13)C]phenylalanine-labeled micellar casein (CAS) protein. Furthermore, primed continuous infusions with l-[ring-(2)H(5)]phenylalanine, l-[1-(13)C]leucine, and l-[ring-(2)H(2)]tyrosine were applied and blood and muscle tissue samples were collected to assess the appearance rate of dietary protein-derived phenylalanine in the circulation and the subsequent muscle protein fractional synthetic rate over a 6-h postprandial period. Protein ingestion resulted in a rapid increase in exogenous phenylalanine appearance in both the young and elderly men. Total exogenous phenylalanine appearance rates (expressed as area under the curve) were 39 +/- 3 mumol.6 h.kg(-1) in the young men and 38 +/- 2 mumol.6 h.kg(-1) in the elderly men (P = 0.73). In accordance, splanchnic amino acid extraction did not differ between young (72 +/- 2%) and elderly (73 +/- 1%) volunteers (P = 0.74). Muscle protein synthesis rates, calculated from the oral tracer, were 0.063 +/- 0.006 and 0.054 +/- 0.004%/h in the young and elderly men, respectively, and did not differ between groups (P = 0.27). We conclude that protein digestion and absorption kinetics and the subsequent muscle protein synthetic response following the ingestion of a large bolus of intact CAS are not substantially impaired in healthy, elderly men.

Elderly Men and Women Benefit Equally From Prolonged Resistance-Type Exercise Training

This study compares the effects of 6 months resistance-type exercise training (three times per week) between healthy elderly women (n = 24; 71±1 years) and men (n = 29; 70±1 years). Muscle mass (dual-energy x-ray absorptiometry-computed tomography), strength (one-repetition maximum), functional capacity (sit-to-stand time), muscle fiber characteristics (muscle biopsies), and metabolic profile (blood samples) were assessed. Leg lean mass (3% ± 1%) and quadriceps cross-sectional area (9% ± 1%) increased similarly in both groups. One-repetition maximum leg extension strength increased by 42% ± 3% (women) and 43% ± 3% (men). Following training, type II muscle fiber size had increased, and a type II muscle fiber specific increase in myonuclear and satellite cell content was observed with no differences between genders. Sit-to-stand time decreased similarly in both groups. Glycemic control and blood lipid profiles improved to a similar extent in both women and men. A generic resistance-type exercise training program can be applied for both women and men to effectively counteract the loss of muscle mass and strength with aging.

Early or advanced stage type 2 diabetes is not accompanied by in vivo skeletal muscle mitochondrial dysfunction

OBJECTIVE Several lines of evidence support a potential role of skeletal muscle mitochondrial dysfunction in the pathogenesis of insulin resistance and/or type 2 diabetes. However, it remains to be established whether mitochondrial dysfunction represents either cause or consequence of the disease. We examined in vivo skeletal muscle mitochondrial function in early and advanced stages of type 2 diabetes, with the aim to gain insight in the proposed role of mitochondrial dysfunction in the aetiology of insulin resistance and/or type 2 diabetes. METHODS Ten long-standing, insulin-treated type 2 diabetes patients, 11 subjects with impaired fasting glucose, impaired glucose tolerance and/or recently diagnosed type 2 diabetes, and 12 healthy, normoglycaemic controls, matched for age and body composition and with low habitual physical activity levels were studied. In vivo mitochondrial function of the vastus lateralis muscle was evaluated from post-exercise phosphocreatine (PCr) recovery kinetics using (31)P magnetic resonance spectroscopy (MRS). Intramyocellular lipid (IMCL) content was assessed in the same muscle using single-voxel (1)H MRS. RESULTS IMCL content tended to be higher in the type 2 diabetes patients when compared with normoglycaemic controls (P=0.06). The(31)P MRS parameters for mitochondrial function, i.e. PCr and ADP recovery time constants and maximum aerobic capacity, did not differ between groups. CONCLUSIONS The finding that in vivo skeletal muscle oxidative capacity does not differ between long-standing, insulin-treated type 2 diabetes patients, subjects with early stage type 2 diabetes and sedentary, normoglycaemic controls suggests that mitochondrial dysfunction does not necessarily represent either cause or consequence of insulin resistance and/or type 2 diabetes.

Tools in the assessment of sarcopenia.

This review provides a framework for the development of an operational definition of sarcopenia and of the potential end points that might be adopted in clinical trials among older adults. While the clinical relevance of sarcopenia is widely recognized, there is currently no universally accepted definition of the disorder. The development of interventions to alter the natural history of sarcopenia also requires consensus on the most appropriate end points for determining outcomes of clinical importance which might be utilized in intervention studies. We review current approaches to the definition of sarcopenia and the methods used for the assessment of various aspects of physical function in older people. The potential end points of muscle mass, muscle strength, muscle power, and muscle fatigue, as well as the relationships between them, are explored with reference to the availability and practicality of the available methods for measuring these end points in clinical trials. Based on current evidence, none of the four potential outcomes in question is sufficiently comprehensive to recommend as a uniform single outcome in randomized clinical trials. We propose that sarcopenia may be optimally defined (for the purposes of clinical trial inclusion criteria as well as epidemiological studies) using a combination of measures of muscle mass and physical performance. The choice of outcome measures for clinical trials in sarcopenia is more difficult; co-primary outcomes, tailored to the specific intervention in question, may be the best way forward in this difficult but clinically important area.

Substantial skeletal muscle loss occurs during only 5 days of disuse.

The impact of disuse on the loss of skeletal muscle mass and strength has been well documented. Given that most studies have investigated muscle atrophy after more than 2 weeks of disuse, few data are available on the impact of shorter periods of disuse. We assessed the impact of 5 and 14 days of disuse on skeletal muscle mass, strength and associated intramuscular molecular signalling responses.

Physical Activity Is the Key Determinant of Skeletal Muscle Mitochondrial Function in Type 2 Diabetes

CONTEXT Conflicting data exist on mitochondrial function and physical activity in type 2 diabetes mellitus (T2DM) development. OBJECTIVE The aim was to assess mitochondrial function at different stages during T2DM development in combination with physical exercise in longstanding T2DM patients. DESIGN AND METHODS We performed cross-sectional analysis of skeletal muscle from 12 prediabetic 11 longstanding T2DM male subjects and 12 male controls matched by age and body mass index. INTERVENTION One-year intrasubject controlled supervised exercise training intervention was done in longstanding T2DM patients. MAIN OUTCOME MEASUREMENTS Extensive ex vivo analyses of mitochondrial quality, quantity, and function were collected and combined with global gene expression analysis and in vivo ATP production capacity after 1 yr of training. RESULTS Mitochondrial density, complex I activity, and the expression of Krebs cycle and oxidative phosphorylation system-related genes were lower in longstanding T2DM subjects but not in prediabetic subjects compared with controls. This indicated a reduced capacity to generate ATP in longstanding T2DM patients only. Gene expression analysis in prediabetic subjects suggested a switch from carbohydrate toward lipid as an energy source. One year of exercise training raised in vivo skeletal muscle ATP production capacity by 21 ± 2% with an increased trend in mitochondrial density and complex I activity. In addition, expression levels of β-oxidation, Krebs cycle, and oxidative phosphorylation system-related genes were higher after exercise training. CONCLUSIONS Mitochondrial dysfunction is apparent only in inactive longstanding T2DM patients, which suggests that mitochondrial function and insulin resistance do not depend on each other. Prolonged exercise training can, at least partly, reverse the mitochondrial impairments associated with the longstanding diabetic state.

Long-standing, insulin-treated type 2 diabetes patients with complications respond well to short-term resistance and interval exercise training

OBJECTIVE To determine the feasibility and the benefits of combined resistance and interval exercise training on phenotype characteristics and skeletal muscle function in deconditioned, type 2 diabetes (T2D) patients with polyneuropathy. DESIGN Short-term, single-arm intervention trial. METHODS Eleven male T2D patients (age: 59.1+/-7.5 years; body mass index: 32.2+/-4.0 kg/m2) performed progressive resistance and interval exercise training thrice a week for 10 weeks. Besides primary diabetes outcome measures, muscle strength (MUST), maximal workload capacity (Wmax), whole-body peak oxygen uptake (VO2peak) and muscle oxidative capacity (MUOX), intramyocellular lipid (IMCL) and glycogen (IMCG) storage, and systemic inflammation markers were determined before and after training. Daily exogenous insulin requirements (EIR) and historic individualized EIR were gathered and analysed. RESULTS MUST and Wmax increased with 17% (90% confidence intervals 9-24%) and 14% (6-21) respectively. Furthermore, mean arterial blood pressure declined with 5.5 mmHg (-9.7 to -1.4). EIR dropped with 5.0 IU/d (-11.5 to 1.5) compared with baseline. A decline of respectively -0.7 mmol/l (-2.9 to 1.5) and -147 micromol/l (-296 to 2) in fasting plasma glucose and non-esterified fatty acids concentrations were observed following the intervention, but these were not accompanied by changes in VO2peak, MUOX, IMCL or IMCG, and blood glycolysated haemoglobin, adiponectin, tumor necrosis factor-alpha and/or cholesterol concentrations. CONCLUSION Short-term resistance and interval exercise training is feasible in deconditioned T2D patients with polyneuropathy and accompanied by moderate improvements in muscle function and blood pressure. Such a specific exercise regimen may provide a better framework for future exercise intervention programmes in the treatment of deconditioned T2D patients.

Neuromuscular electrical stimulation prevents muscle disuse atrophy during leg immobilization in humans

Short periods of muscle disuse, due to illness or injury, result in substantial skeletal muscle atrophy. Recently, we have shown that a single session of neuromuscular electrical stimulation (NMES) increases muscle protein synthesis rates. The aim was to investigate the capacity for daily NMES to attenuate muscle atrophy during short‐term muscle disuse.

The production of intrinsically labeled milk protein provides a functional tool for human nutrition research

Oral or intravenous administration of labeled, free amino acids does not allow the direct assessment of protein digestion and absorption kinetics following dietary protein intake. Consequently, dietary protein sources with labeled amino acids incorporated within the protein are required. The aim of this study was to produce milk proteins intrinsically labeled with l-[1-(13)C]phenylalanine that would allow the assessment of protein digestion and absorption kinetics and the subsequent muscle protein synthetic response to dietary protein intake in vivo in humans. Two Holstein cows (body weight of 726 +/- 38 kg) were continuously infused with l-[1-(13)C]phenylalanine at 402 micromol/min for 44 to 48 h, during and after which plasma samples and milk were collected. After milk protein separation, casein was used in a subsequent human proof-of-principle experiment. Two healthy males (aged 61 +/- 1 yr; body mass index of 22.4 +/- 0.1 kg/m(2)) ingested 35 g of casein highly enriched with [1-(13)C] phenylalanine. Plasma samples were collected at regular intervals, and skeletal muscle biopsies were collected before and 6 h after casein ingestion. In the initial experiment, a total of 5.83 kg of l-[1-(13)C]phenylalanine-enriched milk protein (casein enrichment was 29.4 molar percent excess) was collected during stable isotope infusion in the cows. In the proof-of-principle study, ingestion of 35 g of intrinsically labeled casein resulted in peak plasma l-[1-(13)C]phenylalanine enrichments within 90 min after protein ingestion (9.75 +/- 1.47 molar percent excess). Skeletal muscle protein synthesis rates calculated over the entire 6-h period averaged 0.058 +/- 0.012%/h. The production of intrinsically labeled milk protein is feasible and provides dietary protein that can be used to investigate protein digestion and absorption and the subsequent muscle protein synthetic response in vivo in humans.

Exercise: the brittle cornerstone of type 2 diabetes treatment

Regular exercise has been recommended for diabetes patients for many years; however, it is not widely used clinically. This may be because of high costs, lack of reimbursement, low compliance and/or absence of proper infrastructure. Alternatively, structured exercise therapy may be underutilised because current guidelines do not include detailed information on the preferred type and intensity of exercise that should be applied to maximise the benefits of exercise for different subgroups of patients with type 2 diabetes. Based on available evidence and our own clinical research experience this article proposes that exercise therapy in type 2 diabetes might be more effective if (1) cardiac rehabilitation programmes served as a model for ‘pre-cardiac diabetes rehabilitation’; (2) resistance exercise were prescribed for sarcopenic or severely deconditioned type 2 diabetes patients; and (3) a multidisciplinary approach and continued exercise training under personal supervision became standard therapy. Nevertheless, more clinical research is warranted to establish the efficacy of an approach that takes into account type 2 diabetes subpopulations at different stages of the disease and with different levels of comorbidity.