Fibromyalgia and Chronic Fatigue Syndromes: A systematic review and meta-analysis of cardiorespiratory fitness and neuromuscular function compared with healthy individuals.

OBJECTIVE: To determine cardiorespiratory fitness and neuromuscular function of people with CFS and FMS compared to healthy individuals. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Medline, CINAHL, AMED, Cochrane Central Register of Controlled Trials (CENTRAL), and PEDro from inception to June 2022. ELIGIBLE CRITERIA FOR SELECTING STUDIES: Studies were included if presenting baseline data on cardiorespiratory fitness and/or neuromuscular function from observational or interventional studies of patients diagnosed with FMS or CFS. Participants were aged 18 years or older, with results also provided for healthy controls. Risk of bias assessment was conducted using the Quality Assessment Tool for Quantitative Studies (EPHPP). RESULTS: 99 studies including 9853 participants (5808 patients; 4405 healthy controls) met our eligibility criteria. Random effects meta-analysis showed lower cardiorespiratory fitness (VO2max, anaerobic threshold, peak lactate) and neuromuscular function (MVC, fatigability, voluntary activation, muscle volume, muscle mass, rate of perceived exertion) in CFS and FMS compared to controls: all with moderate to high effect sizes. DISCUSSION: Our results demonstrate lower cardiorespiratory fitness and muscle function in those living with FMS or CFS when compared to controls. There were indications of dysregulated neuro-muscular interactions including heightened perceptions of effort, reduced ability to activate the available musculature during exercise and reduced tolerance of exercise. TRAIL REGISTRATION: PROSPERO registration number: (CRD42020184108).

Circulating testosterone and dehydroepiandrosterone are associated with individual motor unit features in untrained and highly active older men.

Long-term exercise training has been considered as an effective strategy to counteract age-related hormonal declines and minimise muscle atrophy. However, human data relating circulating hormone levels with motor nerve function are scant. The aims of the study were to explore associations between circulating sex hormone levels and motor unit (MU) characteristics in older men, including masters athletes competing in endurance and power events. Forty-three older men (mean ± SD age: 69.9 ± 4.6 years) were studied based on competitive status. The serum concentrations of dehydroepiandrosterone (DHEA), total testosterone (T) and estradiol were quantified using liquid chromatography mass spectrometry. Intramuscular electromyographic signals were recorded from vastus lateralis (VL) during 25% of maximum voluntary isometric contractions and processed to extract MU firing rate (FR), and motor unit potential (MUP) features. After adjusting for athletic status, MU FR was positively associated with DHEA levels (p = 0.019). Higher testosterone and estradiol were associated with lower MUP complexity; these relationships remained significant after adjusting for athletic status (p = 0.006 and p = 0.019, respectively). Circulating DHEA was positively associated with MU firing rate in these older men. Higher testosterone levels were associated with reduced MUP complexity, indicating reduced electrophysiological temporal dispersion, which is related to decreased differences in conduction times along axonal branches and/or MU fibres. Although evident in males only, this work highlights the potential of hormone administration as a therapeutic interventional strategy specifically targeting human motor units in older age.

Cross-talk between motor neurons and myotubes via endogenously secreted neural and muscular growth factors.

Neuromuscular junction (NMJ) research is vital to advance the understanding of neuromuscular patho-physiology and development of novel therapies for diseases associated with NM dysfunction. In vivo, the micro-environment surrounding the NMJ has a significant impact on NMJ formation and maintenance via neurotrophic and differentiation factors that are secreted as a result of cross-talk between muscle fibers and motor neurons. Recently we showed the formation of functional NMJs in vitro in a co-culture of immortalized human myoblasts and motor neurons from rat-embryo spinal-cord explants, using a culture medium free from serum and neurotrophic or growth factors. The aim of this study was to assess how functional NMJs were established in this co-culture devoid of exogenous neural growth factors. To investigate this, an ELISA-based microarray was used to compare the composition of soluble endogenously secreted growth factors in this co-culture with an a-neural muscle culture. The levels of seven neurotrophic factors brain-derived neurotrophic factor (BDNF), glial-cell-line-derived neurotrophic factor (GDNF), insulin-like growth factor-binding protein-3 (IGFBP-3), insulin-like growth factor-1 (IGF-1), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), and vascular endothelial growth factor (VEGF) were higher (p < 0.05) in the supernatant of NMJ culture compared to those in the supernatant of the a-neural muscle culture. This indicates that the cross-talk between muscle and motor neurons promotes the secretion of soluble growth factors contributing to the local microenvironment thereby providing a favourable regenerative niche for NMJs formation and maturation.

Implementing a system-wide cancer prehabilitation programme: The journey of Greater Manchester's 'Prehab4cancer'.

Patients undergoing major cancer interventions such as major surgical resection, chemotherapy, radiotherapy, and immunotherapy are prone to the adverse effects of their cancer, as well as to the side effects of the treatments designed to cure them. The Prehabilitation process supports cancer patients in preparing for the physiological challenges of their cancer treatments, whilst aiming to shorten recovery time, reduce peri-operative complications and improve compliance with non-surgical treatments. Prehabilitation will be most useful in older patients. Greater Manchester Integrated Care system is the first regional system in the UK to introduce delivery of system-wide, large scale physical activity supported multi-modal prehabilitation and recovery programme, Prehab4Cancer as a standard of care for cancer patients. It builds upon the successful implementation of Enhanced Recovery After Surgery + programme to improve surgical care in Greater Manchester. During this review we describe the journey to develop a system wide prehabilitation model for patients with cancer. Prehab4Cancer to date has focused on robust co-design, development, and implementation of an effective service model with attention paid to stakeholder engagement. This has led to receipt of high numbers of referrals from across Greater Manchester for the all the cancer groups involved. The successful implementation of the P4C pathway in GM presents a best practice model that might be adopted by other local and combined authority areas nationally.

Absence of an aging-related increase in fiber type grouping in athletes and non-athletes.

The aging-related loss of muscle mass is thought to be partly attributable to motor neuron loss and motor unit remodeling that result in fiber type grouping. We examined fiber type grouping in 19- to 85-year-old athletes and non-athletes and evaluated to which extent any observed grouping is explained by the fiber type composition of the muscle. Since regular physical activity may stimulate reinnervation, we hypothesized that fiber groups are larger in master athletes than in age-matched non-athletes. Fiber type grouping was assessed in m. vastus lateralis biopsies from 22 young (19-27 years) and 35 healthy older (66-82 years) non-athletes, and 14 young (20-29 years), 51 middle-aged (38-65 years), and 31 older (66-85 years) athletes. An "enclosed fiber" was any muscle fiber of a particular type surrounded by fibers of the same type only. A fiber type group was defined as a group of fibers with at least one enclosed fiber. Only type II fiber cross-sectional area (FCSA) showed an age-related decline that was greater in athletes (P < .001) than in non-athletes (P = .012). There was no significant age-related effect on fiber group size or fiber group number in athletes or non-athletes, and the observed grouping was similar to that expected from the fiber type composition. At face value, these observations do 1) neither show evidence for an age-related loss and remodeling of motor units nor 2) improved reinnervation with regular physical activity, but 3) histological examination may not reveal the full extent of aging-related motor unit remodeling.

Nutrient pattern analysis in critically ill patients using Omics technology (NAChO) - Study protocol for a prospective observational study.

INTRODUCTION: Intensive care unit-acquired weakness (ICU-AW) is often observed in critically ill patients with prolonged intensive care unit (ICU) stay. We hypothesized that evolving metabolic abnormalities during prolonged ICU stay are reflected by changing nutrient patterns in blood, urine and skeletal muscle, and that these patterns differ in patients with/without ICU-AW and between patients with/without sepsis. METHODS: In a prospective single-center observational trial, we aim to recruit 100 critically ill patients (ICU length of stay ≥ 5 days) with severe sepsis/septic shock ("sepsis group", n = 50) or severe head trauma/intracerebral hemorrhage ("CNS group", n = 50). Patients will be sub-grouped for presence or absence of ICU-AW as determined by the Medical Research Council sum score. Blood and urine samples will be collected and subjected to comprehensive nutrient analysis at different time points by targeted quantitative mass spectrometric methods. In addition, changes in muscular tissue (biopsy, when available), muscular architecture (ultrasound), electrophysiology, body composition analyses (bioimpedance, cerebral magnetic resonance imaging), along with clinical status will be assessed. Patients will be followed-up for 180 and 360 days including assessment of quality of life. DISCUSSION: Key objective of this trial is to assess changes in nutrient pattern in blood and urine over time in critically ill patients with/without ICU-AW by using quantitative nutrient analysis techniques. Peer-reviewed published NAChO data will allow for a better understanding of metabolic changes in critically ill patients on standard liquid enteral nutrition and will likely open up new avenues for future therapeutic and nutritional interventions.

Coupling between skeletal muscle fiber size and capillarization is maintained during healthy aging.

BACKGROUND: As muscle capillarization is related to the oxidative capacity of the muscle and the size of muscle fibres, capillary rarefaction may contribute to sarcopenia and functional impairment in older adults. Therefore, it is important to assess how ageing affects muscle capillarization and the interrelationship between fibre capillary supply with the oxidative capacity and size of the fibres. METHODS: Muscle biopsies from healthy recreationally active young (22 years; 14 men and 5 women) and older (74 years; 22 men and 6 women) people were assessed for muscle capillarization and the distribution of capillaries with the method of capillary domains. Oxidative capacity of muscle fibres was assessed with quantitative histochemistry for succinate dehydrogenase (SDH) activity. RESULTS: There was no significant age-related reduction in muscle fibre oxidative capacity. Despite 18% type II fibre atrophy (P = 0.019) and 23% fewer capillaries per fibre (P < 0.002) in the old people, there was no significant difference in capillary distribution between young and old people, irrespective of sex. The capillary supply to a fibre was primarily determined by fibre size and only to a small extent by oxidative capacity, irrespective of age and sex. Based on SDH, the maximal oxygen consumption supported by a capillary did not differ significantly between young and old people. CONCLUSIONS: The similar quantitative and qualitative distribution of capillaries within muscle from healthy recreationally active older people and young adults indicates that the age-related capillary rarefaction, which does occur, nevertheless maintains the coupling between skeletal muscle fibre size and capillarization during healthy ageing.

Assessment of maximal handgrip strength: how many attempts are needed?

BACKGROUND: Handgrip strength (HGS) is used to identify individuals with low muscle strength (dynapenia). The influence of the number of attempts on maximal HGS is not yet known and may differ depending on age and health status. This study aimed to assess how many attempts of HGS are required to obtain maximal HGS. METHODS: Three cohorts (939 individuals) differing in age and health status were included. HGS was assessed three times and explored as continuous and dichotomous variable. Paired t-test, intraclass correlation coefficients (ICC) and Bland-Altman analysis were used to test reproducibility of HGS. The number of individuals with misclassified dynapenia at attempts 1 and 2 with respect to attempt 3 were assessed. RESULTS: Results showed the same pattern in all three cohorts. Maximal HGS at attempts 1 and 2 was higher than at attempt 3 on population level (P < 0.001 for all three cohorts). ICC values between all attempts were above 0.8, indicating moderate to high reproducibility. Bland-Altman analysis showed that 41.0 to 58.9% of individuals had the highest HGS at attempt 2 and 12.4 to 37.2% at attempt 3. The percentage of individuals with a maximal HGS above the gender-specific cut-off value at attempt 3 compared with attempts 1 and 2 ranged from 0 to 50.0%, with a higher percentage of misclassification in middle-aged and older populations. CONCLUSIONS: Maximal HGS is dependent on the number of attempts, independent of age and health status. To assess maximal HGS, at least three attempts are needed if HGS is considered to be a continuous variable. If HGS is considered as a discrete variable to assess dynapenia, two attempts are sufficient to assess dynapenia in younger populations. Misclassification should be taken into account in middle-aged and older populations.

Circulating levels of adipokines and IGF-1 are associated with skeletal muscle strength of young and old healthy subjects.

It is known that adipose tissue mass increases with age, and that a number of hormones, collectively called adipokines, are produced by adipose tissue. For most of them it is not known whether their plasmatic levels change with age. Moreover, it is known that adipose tissue infiltration in skeletal muscle is related to sarcopenia and loss of muscle strength. In this study we investigated the age-related changes of representative adipokines and insulin-like growth factor (IGF)-1 and their effect on muscle strength. We studied the association between circulating levels of adiponectin, leptin, resistin and IGF-1 and muscle strength. This cross-sectional study included 412 subjects of different age (152 subjects aged 18-30 years and 260 subjects aged 69-81 years) recruited within the framework of the European research network project "Myoage". The levels of adiponectin (both in male and female subjects) and leptin (only in males) were significantly higher in old subjects compared to young, while those of IGF-1 were lower in old subjects. In old subjects adiponectin, resistin and the resistin/IGF-1 ratio (but not IGF-1 alone) were inversely associated with quadriceps torque, while only adiponectin was inversely associated with handgrip strength independently from percentage of fat mass, height, age, gender and geographical origin. The ratio of leptin to adiponectin was directly associated with handgrip strength in both young and old subjects. These results suggest that in humans the age-associated loss of strength is associated with the levels of representative adipokines and IGF-1.

The training stimulus experienced by the leg muscles during cycling in humans.

Considerable variability exists between people in their health- and performance-related adaptations to conventional endurance training. We hypothesized that some of this variability might be due to differences in the training stimulus received by the working muscles. In 71 young sedentary women we observed large variations in the ratio of one-leg cycling muscle aerobic capacity (V(O2peak)) to two-leg cycling whole-body maximal oxygen uptake (V(O2max); Ratio(1:2); range 0.58-0.96). The variability in Ratio(1:2) was primarily due to differences between people in one-leg V(O2peak) (r = 0.71, P < 0.0005) and was not related to two-leg V(O2max) (r = 0.15, P = 0.209). Magnetic resonance imaging (n = 30) and muscle biopsy sampling (n = 20) revealed that one-leg V(O2peak) was mainly determined by muscle volume (r = 0.73, P < 0.0005) rather than muscle fibre type or oxidative capacity. A high one-leg V(O2peak) was associated with favourable lipoprotein profiles (P = 0.033, n = 24) but this was not the case for two-leg V(O2max). Calculations based on these data suggest that conventional two-leg exercise at 70% V(O2max) requires subjects with the lowest Ratio(1:2) to work their legs at 60% of single-leg V(O2peak), whilst those with the highest Ratio(1:2) work their legs at only 36% of maximum. It was concluded that endurance training carried out according to current guidelines will result in highly variable training stimuli for the leg muscles and variable magnitudes of adaptation. These conclusions have implications for the prescription of exercise to improve health and for investigations into the genetic basis of muscle adaptations.