Arnold de Haan

Altered Ca2+ responses in muscles with combined mitochondrial and cytosolic creatine kinase deficiencies

We have blocked creatine kinase (CK)-mediated phosphocreatine (PCr) -->/<-- ATP transphosphorylation in skeletal muscle by combining targeted mutations in the genes encoding mitochondrial and cytosolic CK in mice. Contrary to expectation, the PCr level was only marginally affected, but the compound was rendered metabolically inert. Mutant muscles in vivo showed significantly impaired tetanic force output, increased relaxation times, altered mitochondrial volume and location, and conspicuous tubular aggregates of sarcoplasmic reticulum membranes, as seen in myopathies with electrolyte disturbances. In depolarized myotubes cultured in vitro, CK absence influenced both the release and sequestration of Ca2+. Our data point to a direct link between the CK-PCr system and Ca2+-flux regulation during the excitation and relaxation phases of muscle contraction.

Attenuated Increase in Maximal Force of Rat Medial Gastrocnemius Muscle after Concurrent Peak Power and Endurance Training

Improvement of muscle peak power and oxidative capacity are generally presumed to be mutually exclusive. However, this may not be valid by using fibre type-specific recruitment. Since rat medial gastrocnemius muscle (GM) is composed of high and low oxidative compartments which are recruited task specifically, we hypothesised that the adaptive responses to peak power training were unaffected by additional endurance training. Thirty rats were subjected to either no training (control), peak power training (PT), or both peak power and endurance training (PET), which was performed on a treadmill 5 days per week for 6 weeks. Maximal running velocity increased 13.5% throughout the training and was similar in both training groups. Only after PT, GM maximal force was 10% higher than that of the control group. In the low oxidative compartment, mRNA levels of myostatin and MuRF-1 were higher after PT as compared to those of control and PET groups, respectively. Phospho-S6 ribosomal protein levels remained unchanged, suggesting that the elevated myostatin levels after PT did not inhibit mTOR signalling. In conclusion, even by using task-specific recruitment of the compartmentalized rat GM, additional endurance training interfered with the adaptive response of peak power training and attenuated the increase in maximal force after power training.

Adenylate kinase 1 gene deletion disrupts muscle energetic economy despite metabolic rearrangement

Efficient cellular energy homeostasis is a critical determinant of muscle performance, providing evolutionary advantages responsible for species survival. Phosphotransfer reactions, which couple ATP production and utilization, are thought to play a central role in this process. Here, we provide evidence that genetic disruption of AK1‐catalyzed β‐phosphoryl transfer in mice decreases the potential of myofibers to sustain nucleotide ratios despite up‐regulation of high‐energy phosphoryl flux through glycolytic, guanylate and creatine kinase phosphotransfer pathways. A maintained contractile performance of AK1‐deficient muscles was associated with higher ATP turnover rate and larger amounts of ATP consumed per contraction. Metabolic stress further aggravated the energetic cost in AK1−/− muscles. Thus, AK1‐catalyzed phosphotransfer is essential in the maintenance of cellular energetic economy, enabling skeletal muscle to perform at the lowest metabolic cost.

Contractile properties and fatigue of quadriceps muscles in multiple sclerosis.

Functional characteristics of electrically stimulated quadriceps muscles of patients with multiple sclerosis (MS) were determined to investigate whether adaptations in muscle properties contribute to the higher fatigability of these patients. The estimated maximal isometric force generating capacity of MS patients was only 11.2% (P < 0.05) lower than control subjects. However, the patients were only able to voluntarily exert 75 ± 22% (n = 12) of their maximal capacity, against 94 ± 6% (n = 7) for the control subjects. There were no differences in muscle speed, suggesting that muscle fiber distribution was not different in the MS patients due to reduced muscle usage. During a series of repeated contractions, greater decrements occurred in isometric force and in maximal rate of force rise in the MS patients (by 31.3 ± 10.3% and 50.1 ± 10.0%, respectively; n = 13) than control subjects (23.8 ± 6.6% and 39.0 ± 8.1%, n = 15), suggesting a lower oxidative capacity. The results indicate that increasing the mass of their muscles by training may help to reduce the excessive muscle fatigue of MS patients.

Sex differences in contractile properties and fatigue resistance of human skeletal muscle

To explore the cause of higher skeletal muscle fatigue resistance in women than men, we used electrically evoked contractions (1 s on, 1 s off, 30 Hz, 2 min), which circumvent motivational bias and allow examination of contractile properties. We compared 29 men [26.5 (7.0) years old; mean (s.d.)] with 35 women [25.4 (7.6) years old]. Strength of the quadriceps muscle was higher in men than women (P < 0.001). The lower maximal rate of relaxation in women (P= 0.002) indicates that their muscles were slower than those of men. The torque declined less in women than in men [37.7 (10.7) versus 29.9 (10.0)%; P= 0.002], and was not related to muscle strength or size, as determined with magnetic resonance imaging. The sex difference in fatigability was also seen when the circulation to the leg was occluded [torque declined 76.9 (10.8) versus 59.5 (16.9)% in men versus women, respectively; P= 0.008]. The maximal rate of relaxation correlated with the fatigability of the muscle under all conditions (correlations ranging from 0.34 to 0.51, P < 0.02). We conclude that the sex‐related difference in skeletal muscle fatigue resistance is not explicable by differences in motivation, muscle size, oxidative capacity and/or blood flow between sexes, but might be related to differences in fibre type composition.

Intrinsic muscle strength and voluntary activation of both lower limbs and functional performance after stroke.

The objective of this study was to assess the nature of muscle weakness in both legs after stroke compared with able‐bodied control individuals and to examine whether there is a relationship between the degree of muscle weakness and coactivation of knee extensors and flexors as well as voluntary activation capacity of knee extensors of both paretic and non‐paretic legs and indices of functional performance. Maximal voluntary isometric torques of knee extensors (MVCe) and flexors (MVCf) were determined in 14 patients (bilaterally) and 12 able‐bodied controls. Simultaneous measurements were made of torque and surface EMG from agonist and antagonist muscles. Coactivation was calculated. Supramaximal triplets were evoked with electrical stimulation to estimate maximal torque capacity and degree of voluntary activation of knee extensors. MVCs, activation and coactivation parameters were correlated to scores of seven functional performance tests. MVCe, MVCf and voluntary activation were lower in paretic lower limb (PL) compared with both non‐paretic lower limb (NL) and control. Besides, all these parameters of NL were also lower than control. Electrically evoked torque capacity of knee extensors of PL was about 60% of both NL and control, which were not significantly different from each other. Strong significant correlations between strength, as well as voluntary activation, and functional performance were found. Coactivation did not correlate well with functional performance. Thus, whereas for NL activation failure can explain weakness, for PL both activation failure and reduced intrinsic torque capacity are responsible for the severe weakness. Activation capacity and muscle strength correlated strongly to functional performance, while coactivation did not.

Prevention of bone loss during 56 days of strict bed rest by side-alternating resistive vibration exercise

Bed rest is a recognized model for muscle atrophy and bone loss in space flight and in clinical medicine. We hypothesized that whole body vibration in combination with resistive exercise (RVE) would be an effective countermeasure. Twenty healthy male volunteers underwent horizontal bed rest for 56 days and were randomly assigned either to a group that performed RVE 11 times per week or to a group that underwent bed rest only (Ctrl). Bone mineral content (BMC) was assessed by peripheral quantitative computed tomography (pQCT) in the tibia and the radius and by dual x-ray absorptiometry (DXA) in the hip and lumbar spine at baseline and at regular intervals during bed rest and a 12-month follow-up. RVE appeared to protect muscle size and function, and it also prevented bone loss (p-values between <0.001 and 0.01). Bone losses were largest in the distal tibia epiphysis, where BMC declined from 421.8 mg/mm (SD 51.3) to 406.6 mg/mm (SD 52.7) in Ctrl, but only from 411.1 mg/mm (SD 56.6) to 409.6 mg/mm (SD 66.7) in RVE. Most of the BMC losses were recovered by 12-month follow-up. Analyses showed that the epiphyseal cortex, rather than spongiosa, depicted the most pronounced changes during bed rest and recovery. These results suggest that the combined countermeasure applied in this study is effective to prevent bone losses from the tibia. This underlines the importance of mechanical usage for the maintenance of the human skeleton.

CYTOARCHITECTURAL AND METABOLIC ADAPTATIONS IN MUSCLES WITH MITOCHONDRIAL AND CYTOSOLIC CREATINE KINASE DEFICIENCIES

We have blocked creatine kinase (CK) mediated phosphocreatine (PCr) ⇄ ATP transphosphorylation in mitochondria and cytosol of skeletal muscle by knocking out the genes for the mitochondrial (ScCKmit) and the cytosolic (M-CK) CK isoforms in mice. Animals which carry single or double mutations, if kept and tested under standard laboratory conditions, have surprisingly mild changes in muscle physiology. Strenuous ex vivo conditions were necessary to reveal that MM-CK absence in single and double mutants leads to a partial loss of tetanic force output. Single ScCKmit deficiency has no noticeable effects but in combination the mutations cause slowing of the relaxation rate. Importantly, our studies revealed that there is metabolic and cytoarchitectural adaptation to CK defects in energy metabolism. The effects involve mutation type-dependent alterations in the levels of AMP, IMP, glycogen and phosphomonoesters, changes in activity of metabolic enzymes like AMP-deaminase, alterations in mitochondrial volume and contractile protein (MHC isoform) profiles, and a hyperproliferation of the terminal cysternae of the SR (in tubular aggregates). This suggests that there is a compensatory resiliency of loss-of-function and redirection of flux distributions in the metabolic network for cellular energy in our mutants.

Adaptive response of human tendon to paralysis

To gain insight into the adaptive response of human tendon to paralysis, we compared the mechanical properties of the in vivo patellar tendon in six men who were spinal cord–injured (SCI) and eight age‐matched, able‐bodied men. Measurements were taken by combining dynamometry, electrical stimulation, and ultrasonography. Tendon stiffness and Youngs modulus, calculated from force–elongation and stress–strain curves, respectively, were lower by 77% (P < 0.01) and 59% (P < 0.05) in the SCI than able‐bodied subjects. The cross‐sectional area (CSA) of the tendon was 17% smaller (P < 0.05) in the SCI subjects, but there was no difference in tendon length between the two groups. Our results indicate that paralysis causes substantial deterioration of the structural and material properties of tendon. This needs to be taken into consideration in the design of electrical stimulation protocols for rehabilitation and experimental purposes, and when interpreting changes in the contractile speed of paralyzed muscle. Muscle Nerve, 2005

Reduced neural drive in bilateral exertions: a performance-limiting factor?

PURPOSE Activity of the motor cortex in one hemisphere reduces the maximum motor outflow of homologous parts of the opposite hemisphere, causing a reduction in the maximum force a muscle can exert when the contralateral homologous muscle is activated concurrently. The purpose of this study was to establish whether this bilateral deficit is large enough to explain limitations in performance in bilateral exertions. METHODS Voluntary force production and neural drive during unilateral and bilateral exertions were compared in three experiments, consisting of unilateral maximum contractions, synchronous bilateral contractions, and asynchronous bilateral contractions of finger flexors and knee extensors. RESULTS Maximum voluntary force was overall about 7% lower in bilateral knee extension as compared with unilateral knee extension (P < 0.001). In finger flexion, a bilateral voluntary force deficit of as much as 20% was found ( P= 0.001). Corresponding deficits in agonist EMG activity were also significant and on average found to be of similar size, though the magnitude of the bilateral deficit in EMG was not consistently related to the magnitude of the bilateral force deficit. In knee extension, a deficit in voluntary activation of 4% (P = 0.003) was demonstrated by means of superimposed tetanic stimulation. The magnitude of this deficit was correlated to the magnitude of the voluntary force deficit (r = 0.80, P= 0.002). The maximum rate of force development in bilateral knee extensions was 13% lower than in a unilateral knee extension (P = 0.002). CONCLUSION These results suggest that deficits in bilateral force production are large enough to constitute an important performance-limiting factor. Furthermore, the data suggest that a reduced neural drive underlies this bilateral deficit.