Muscle fiber-type distribution, fiber-type-specific damage, and the Pompe disease phenotype.

Pompe disease is a lysosomal storage disorder caused by acid α-glucosidase deficiency and characterized by progressive muscle weakness. Enzyme replacement therapy (ERT) has ameliorated patients' perspectives, but reversal of skeletal muscle pathology remains a challenge. We studied pretreatment biopsies of 22 patients with different phenotypes to investigate to what extent fiber-type distribution and fiber-type-specific damage contribute to clinical diversity. Pompe patients have the same fiber-type distribution as healthy persons, but among nonclassic patients with the same GAA mutation (c.-32-13T>G), those with early onset of symptoms tend to have more type 2 muscle fibers than those with late-onset disease. Further, it seemed that the older, more severely affected classic infantile patients and the wheelchair-bound and ventilated nonclassic patients had a greater proportion of type 2x muscle fibers. However, as in other diseases, this may be caused by physical inactivity of those patients.

Murine muscles deficient in creatine kinase tolerate repeated series of high-intensity contractions.

Murine muscles lacking both mitochondrial (Mi-CK) and cytoplasmic (MM-CK) creatine kinase (CK-/-) show depressed mechanical performance in association with low muscle ATP and enhanced IMP content. The aims of the present study were to elucidate the possible role of low ATP and high IMP content in impairment of mechanical performance in CK-/- mice and to establish whether CK-/- muscles are able to sustain repeated series of high-intensity contractions. The dorsal flexors of CK-/- and control mice were subjected in situ to two series of 12 tetanic contractions using a custom-made mouse isometric dynamometer. The muscle content of high-energy phosphates was analysed by HPLC. ATP content declined from 20.6+/-1.9 to 15.5+/-2.4 micromol x g(-1) dry weight (d.w.); IMP content increased from 1.2+/-0.4 to 2.4+/-1.1 micromol x g(-1) d.w. during the first contraction series in CK-/- muscle. Despite these unfavourable changes, maximal torque developed during the first contraction of either series did not differ, indicating that the altered content of ATP and IMP does not play a decisive role in impaired mechanical performance in CK-/- mice. The relative decline in torque during the two series did not differ in CK-/- (-20.4+/-6.6 vs. -23.8+/-9.9%). In contrast, wild-type (WT) muscles showed a significantly more pronounced decline during the second series (-12.3+/-7.4 vs. -20.1+/-6.8%). Muscle ATP and IMP content did not change in CK-/-, whereas in WT IMP content increased significantly during the second contraction series. These findings indicate that CK-/- tolerate repeated series of high-intensity contractions better than WT, while in CK-/- muscle an additional source of energy is mobilised to regenerate ATP during the second series.

The effect of seat tilting on pelvic position, balance control, and compensatory postural muscle use in paraplegic subjects.

OBJECTIVE: To study the effect of seat tilting on pelvic tilt, balance control, and postural muscle use in persons with a thoracic spinal cord injury (SCI). DESIGN: Cross-sectional group study. SETTING: Rehabilitation centers and rehabilitation hospital departments. PATIENTS: Ten complete high thoracic SCI (level T2-8) patients, 10 complete low thoracic SCI (level T9-12) patients, and 10 matched able-bodied controls. INTERVENTION: A 10 degrees forward inclination of the seat. MAIN OUTCOME MEASURES: Pelvic tilt, center of pressure displacement, and muscle activity. RESULTS: Anterior tilting of the pelvis as a result of forward inclination of the seat could not be shown, either in persons with or without SCI. Balance control was not influenced by forward inclination of the seat. Participants' overall muscle activity decreased while they were seated in the chair with the forwardly inclined seat. CONCLUSIONS: Evidence provided by the kinematic and electromyographic data is not sufficient to develop a protocol for wheelchair prescription on the basis of pelvic positioning.

Impaired muscular contractile performance and adenine nucleotide handling in creatine kinase-deficient mice.

Creatine kinase (CK) forms a small family of isoenzymes playing an important role in maintaining the concentration of ATP and ADP in muscle cells. To delineate the impact of a lack of CK activity, we studied contractile performance during a single maximal tetanic contraction and during 12 repeated tetanic contractions of intact dorsal flexors of CK knockout (CK(-/-)) mice. To investigate the effect on ATP regeneration, muscular high-energy phosphate content was determined at rest, immediately after the contraction series, and after a 60-s recovery period. Maximal torque of the dorsal flexors was significantly lower in CK(-/-) mice than in wild-type animals, i.e., 23.7 +/- 5.1 and 33.3 +/- 6.8 mN. m. g(-1) wet wt, respectively. Lower muscle ATP (20.1 +/- 1.4 in CK(-/-) vs. 28.0 +/- 2.1 micromol/g dry wt in controls) and higher IMP (1.2 +/- 0.5 in CK(-/-) vs. 0.3 +/- 0.1 micromol/g dry wt in controls) levels at the onset of contraction may contribute to the declined contractility in CK(-/-) mice. In contrast to wild-type muscles, ATP levels could not be maintained during the series of 12 tetanic contractions of dorsal flexors of CK(-/-) mice and dropped to 15.5 +/- 2.4 micromol/g dry wt. The significant increase in tissue IMP (2.4 +/- 1.1 micromol/g dry wt) content after the contraction series indicates that ATP regeneration through adenylate kinase was not capable of fully compensating for the lack of CK. ATP regeneration via the adenylate kinase pathway is a likely cause of reduced basal adenine nucleotide levels in CK(-/-) mice.

Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration.

Hypoxia stimulates angiogenesis through the binding of hypoxia-inducible factors to the hypoxia-response element in the vascular endothelial growth factor (Vegf) promotor. Here, we report that deletion of the hypoxia-response element in the Vegf promotor reduced hypoxic Vegf expression in the spinal cord and caused adult-onset progressive motor neuron degeneration, reminiscent of amyotrophic lateral sclerosis. The neurodegeneration seemed to be due to reduced neural vascular perfusion. In addition, Vegf165 promoted survival of motor neurons during hypoxia through binding to Vegf receptor 2 and neuropilin 1. Acute ischemia is known to cause nonselective neuronal death. Our results indicate that chronic vascular insufficiency and, possibly, insufficient Vegf-dependent neuroprotection lead to the select degeneration of motor neurons.

Acute and sustained effects of isometric and lengthening muscle contractions on high-energy phosphates and glycogen metabolism in rat tibialis anterior muscle.

Previous studies have shown that lengthening contractions, in contrast to isometric contractions, readily result in sustained malfunctioning of the exercised muscles. The present study was performed to investigate whether an exercise period with many (240) lengthening contractions (LC) results in alterations in muscle high-energy phosphates and inosine monophosphate (IMP) content, different from muscles performing a few (60) lengthening or a few (60) or many (240) isometric contractions (IC). Moreover, we sought for a possible cause(s) of the inability to replenish muscle glycogen stores following LC. Rat tibialis anterior muscles were subjected in vivo to either 60 or 240 LC or IC. Structural muscle damage occurred only after 240 LC. The fact that tissue glycogen levels declined to a similar extent during LC and IC suggests that the energy demand was comparable during both types of exercise. Nevertheless, the observation that on the one hand tissue stores of adenine nucleotides showed a greater decline, and on the other hand the tissue content of IMP increased to a significantly higher level after LC than after IC, clearly indicates that muscle energy metabolism is more disturbed during LC than during IC. The high tissue levels of IMP may contribute to impaired mechanical function as previously observed in muscles subjected to LC. In contrast to 240 IC, 24 hours after 240 LC, tissue glycogen stores and high-energy phosphate levels were not restored to control values. The present findings indicate that depressed glycogen synthase activity and impaired activity of the mitochondrial marker enzyme cytochrome C oxidase probably contribute to a continuous disturbance of energy metabolism in the exercised muscles during the 24 hours following 240 LC.