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Muscle atrophy is clearly related to a loss of muscle torque, but the reduction in muscle size cannot entirely account for the decrease in muscle torque. Reduced neural input to muscle has been proposed to account for much of the remaining torque deficits after disuse or immobilization. The purpose of this investigation was to assess the relative contributions of voluntary muscle activation failure and muscle atrophy to loss of plantarflexor muscle torque after immobilization. Nine subjects (ages 19-23) years with unilateral ankle malleolar fractures were treated by open reduction-internal fixation and 7 weeks of cast immobilization. Subjects participated in 10 weeks of rehabilitation that focused on both strength and endurance of the plantarflexors. Magnetic resonance imaging, isometric plantarflexor muscle torque and activation (interpolated twitch technique) measurements were performed at 0, 5, and 10 weeks of rehabilitation. Following immobilization, voluntary muscle activation (56.8 AE 16.3%), maximal cross-sectional area (CSA) (35.3 AE 7.6cm 2 ), and peak torque (26.2 AE 12.7N-m) were all significantly decreased ( p < 0.0056) compared to the uninvolved limb (98.0 AE 2.3%, 48.0 AE 6.8 cm 2 , and 105.2 AE 27.0 N-m, respectively). During 10 weeks of rehabilitation, muscle activation alone accounted for 56.1% of the variance in torque ( p < 0.01) and muscle CSA alone accounted for 35.5% of the variance in torque ( p < 0.01). Together, CSA and muscle activation accounted for 61.5% of the variance in torque ( p < 0.01). The greatest gains in muscle activation were made during the first 5 weeks of rehabilitation. Both increases in voluntary muscle activation and muscle hypertrophy contributed to the recovery in muscle strength following immobilization, with large gains in activation during the first 5 weeks of rehabilitation. In contrast, muscle CSA showed fairly comparable gains throughout both the early and later phase of rehabilitation. ß

Oxidative slow skeletal muscle contains carbonic anhydrase III in high concentration, but its primary function remains unknown. To determine whether its lack handicaps energy metabolism and/or acid elimination, we measured the intracellular pH and energy phosphates by 31 P magnetic resonance spectroscopy in hind limb muscles of wild-type and CA III knockout mice during and after ischemia and intense exercise (electrical stimulation). Thirty minutes of ischemia caused phosphocreatine (PCr) to fall and Pi to rise while pH and ATP remained constant in both strains of mice. PCr and Pi kinetics during ischemia and recovery were not significantly different between the two genotypes. From this we conclude that under neutral pH conditions resting muscle anaerobic metabolism, the rate of the creatine kinase reaction, intracellular buffering of protons, and phosphorylation of creatine by mitochondrial oxygen metabolism are not influenced by the lack of CA III. Two minutes of intense stimulation of the mouse gastrocnemius caused PCr, ATP, and pH to fall and ADP and P i to rise, and these changes, with the exception of ATP, were all significantly larger in the CA III knockouts. The rate of return of pH and ADP to control values was the same in wild-type and mutant mice, but in the mutants PCr and Pi recovery were delayed in the first minute after stimulation. Because the tension decrease during fatigue is known to be the same in the two genotypes, we conclude that a lack of CA III impairs mitochondrial ATP synthesis.mitochondrial ATP synthesis S keletal muscle contains at least four isozymes of carbonic anhydrase (EC 4.2.1.1): CA II, CA III, CA IV, and CA V (1). CA II, the high-activity enzyme found in erythrocytes, is present in the sarcoplasm available to accelerate the removal of acid as CO 2 . CA IV is bound to the sarcolemma and facilitates lactate transport across the sarcolemma. CA V, in the mitochondria, accelerates the metabolism of pyruvate (2). CA III is present in the highest concentration of any of the carbonic anhydrases, as much as 2% of wet weight in slow oxidative muscle (type 1) (3), but its function is unknown. It is only minimally present in fast glycolytic (type 2) muscle (4). Changes in CA III levels have been reported when skeletal muscle is undergoing remodeling due to training (5) or inactivity (6, 7). CA III has a molecular weight of Ϸ30,000, similar to that of isozymes CA II, CA IV, and CA V, but accelerates CO 2 hydration at only 1/60th as much as human erythrocyte CA II and is 30,000 times less sensitive to acetazolamide (a widely used sulfonamide inhibitor) (8). It has two reactive surface cysteines, whereas the other muscle isozymes have none, indicating that it may have a role in the regulation of oxidative stress (9). In addition, CA III itself interacts directly with glutathione and is highly modified during lipid peroxidation (10, 11). Despite many experimental studies, no convincing rationale for the presence, preservation, and production of the large concentration of CA III in oxidative ...

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Cast immobilization is associated with decreases in muscle contractile area, specific force, and functional ability. The pathophysiological processes underlying the loss of specific force production as well as the role of metabolic alterations are not well understood. The aim of this study was to quantify changes in the resting energy-rich phosphate content and specific force production after immobilization. (31)P-magnetic resonance spectroscopy, three-dimensional magnetic resonance imaging, and isometric strength testing were performed in healthy subjects and patients with an ankle fracture after 7 wk of immobilization and during rehabilitation. Muscle biopsies were obtained in a subset of patients. After immobilization, there was a significant decrease in the specific plantar flexor torque and a significant increase in the inorganic phosphate (P(i)) concentration (P < 0.001) and the P(i)-to-phosphocreatine (PCr) ratio (P < 0.001). No significant change in the PCr content or basal pH was noted. During rehabilitation, both the P(i) content and the P(i)-to-PCr ratio decreased and specific torque increased, approaching control values after 10 wk of rehabilitation. Regression analysis showed an inverse relationship between the in vivo P(i) concentration and specific torque (r = 0.65, P < 0.01). In vitro force mechanics performed on skinned human muscle fibers demonstrated that varying the P(i) levels within the ranges observed across individuals in vivo (4-10 mM) changed force production by approximately 16%. In summary, our findings clearly depict a change in the resting energy-rich phosphate content of skeletal muscle with immobilization, which may negatively impact its force generation.

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Study Design: Cross-sectional study. Objective: (1) To quantify intramyocellular lipid (IMCL) content of the soleus muscle. (2) To assess the T 2 relaxation rates in the lower extremity skeletal muscles in persons with incomplete spinal cord injury (SCI). Setting: Academic Institution, Florida. Methods: Eight subjects (42 ± 10 years old; 70 ± 12 kg; 176 ± 10 cm) with chronic (17 ± 9 months post injury) motor SCI (C4-T12; ASIA C or D) and eight matched healthy controls were tested. Localized unsuppressed proton spectroscopy (H-MRS) was performed to estimate total lipid content and individual lipid components; IMCL and extramyocellular lipid (EMCL) from the soleus muscle. T 2 -weighted imaging of lower extremity muscles yielded muscle T 2 rates. Results: The IMCL content of the soleus muscle was 3.3 times higher in the patient group as compared to controls (P ¼ 0.002; 0.0401 (0.0234-0.0849) versus 0.0123 (0.0090-0.0175)). Similarly, EMCL measures were 4.5 times higher as compared to the controls (P ¼ 0.002). Significant differences were observed in the T 2 relaxation times of the soleus and gastrocnemius muscles (Po0.05). Conclusion:The increased levels of IMCL might interfere with the glucose uptake in skeletal muscle; potentially predisposing persons with incomplete SCI to the development of peripheral insulin resistance. Marked elevations in the T 2 relaxation times of the locomotor muscles are reflective of an altered muscle composition.