Whole muscle strength and cross-sectional area (WMCSA), and contractile properties of chemically skinned segments from single fibers of the quadriceps were studied in 7 young men (YM, 36.5 +/- 3. 0 yr), 12 older men (OM, 74.4 +/- 5.9 yr), and 12 older women (OW, 72.1 +/- 4.3 yr). WMCSA was smaller in OM compared with YM (56.1 +/- 10.1 vs. 79.7 +/- 13.1 cm(2); P = 0.031) and in OW (44.9 +/- 7.5; P < 0.003) compared with OM. Age-related, but not sex-related, differences in strength were eliminated after adjusting for WMCSA. Maximal force was measured in 552 type I and 230 type IIA fibers. Fibers from YM (type I = 725 +/- 221; type IIA = 792 +/- 271 microN) were stronger (P < 0.001) than fibers from OM (I = 505 +/- 179; IIA = 577 +/- 262 microN) even after correcting for size. Type IIA fibers were stronger (P < 0.005) than type I fibers in YM and OM but not in OW (I = 472 +/- 154; IIA = 422 +/- 97 microN). Sex-related differences in type I and IIA fibers were dependent on fiber size. In conclusion, differences in WMCSA explain age-related differences in strength. An intrinsic defect in contractile proteins could explain weakness in single fibers from OM. Sex-related differences exist at the whole muscle and single fiber levels.

Cross-sectional studies are likely to underestimate age-related changes in skeletal muscle strength and mass. The purpose of this longitudinal study was to assess whole muscle and single muscle fiber alterations in the same cohort of 12 older (mean age: start of study 71.1+/-5.4 yr and end of study 80+/-5.3 yr) volunteers (5 men) evaluated 8.9 yr apart. No significant changes were noted at follow-up in body weight, body mass index, and physical activity. Muscle strength, evaluated using isokinetic dynamometry, and whole muscle specific force of the knee extensors were significantly lower at follow-up. This was accompanied by a significant reduction (5.7%) in cross-sectional area of the total anterior muscle compartment of the thigh as evaluated by computed tomography. Muscle histochemistry showed no significant changes in fiber type distribution or fiber area. Experiments with chemically skinned single muscle fibers (n=411) demonstrated no change in type I fiber size but an increase in IIA fiber diameter. A trend toward an increase in maximal force in both fiber types was observed. Maximum unloaded shortening velocity did not change. In conclusion, single muscle fiber contractile function may be preserved in older humans in the presence of significant alterations at the whole muscle level. This suggests that surviving fibers compensate to partially correct muscle size deficits in an attempt to maintain optimal force-generating capacity.

Overuse injuries develop when repetitive stress to bone and musculotendinous structures damages tissue at a greater rate than that at which the body can repair itself. A combination of extrinsic factors, such as training errors and environmental factors, and intrinsic or anatomical factors, such as bony alignment of the extremities, flexibility deficits and ligamentous laxity, predispose athletes to develop overuse injuries. Malalignant of the lower extremity, including excess femoral anteversion, increased Q angle, lateral tibial torsion, tibia vara, genu varum or valgum, subtalar varus and excessive pronation are frequently cited as predisposing to knee extensor mechanism overuse injuries. These and other forms of malalignment have also been implicated in iliotibial band syndrome, medial tibial stress syndrome, lower extremity stress fractures and plantar fasciitis. Muscle inflexibility aggravates and predisposes to the development of a variety of overuse injuries, especially those occurring in children and adolescents, including the traction apophysitises. Flexibility deficits may be improved by an appropriate stretching programme. Unfortunately, lower extremity malalignment is less amenable to intervention. Orthotics are often prescribed to improve lower extremity alignment. However, studies have not shown that orthotics have any effect on knee alignment and, while they can alter subtalar joint alignment, the clinical benefit of this remains unclear. Awareness of anatomical factors that may predispose to overuse injuries allows the clinician to develop individual prehabilitation programmes designed to decrease the risk of overuse injury. In addition, the clinician can advise the athlete on the importance of avoiding extrinsic factors that may also predispose to overuse injury.

Objective-Amyotrophic lateral sclerosis (ALS) is a devastating, and currently incurable, neuromuscular disease in which oxidative stress and mitochondrial impairment are contributing to neuronal loss. Coenzyme Q10 (CoQ10), an antioxidant and mitochondrial cofactor, has shown promise in ALS transgenic mice, and in clinical trials for neurodegenerative diseases other than ALS. Our aims were to choose between two high doses of CoQ10 for ALS, and to determine if it merits testing in a Phase III clinical trial.Methods-We designed and implemented a multi-center trial with an adaptive, two-stage, biasadjusted, randomized, placebo-controlled, double-blind, Phase II design (n=185). The primary outcome in both stages was decline in the ALS Functional Rating Scale-revised (ALSFRSr) score over 9 months. Stage 1 (dose selection, 35 participants per group) compared CoQ10 doses of 1,800 and 2,700 mg/day. Stage 2 (futility test, 75 patients per group) compared the dose selected in Stage 1 against placebo.Results-Stage 1 selected the 2,700 mg dose. In Stage 2, the pre-specified primary null hypothesis that this dose is superior to placebo was not rejected. It was rejected, however, in an Kaufmann et al. Page 2Ann Neurol. Author manuscript; available in PMC 2010 August 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript accompanying pre-specified sensitivity test, and further supplementary analyses. Pre-specified secondary analyses showed no significant differences between CoQ10 at 2,700 mg/day and placebo. There were no safety concerns.Interpretation-CoQ10 at 2,700 mg daily for 9 months shows insufficient promise to warrant Phase III testing. Given this outcome, the adaptive Phase II design incorporating a dose selection and a futility test avoided the need for a much larger conventional Phase III trial.ALS is an orphan disease with an average annual incidence rate of 1 to 2 per 100,000 person-years, 1-3 and, because the disease typically leads to death within 2 to 4 years of onset, 4 a relatively low prevalence of 4-6 per 100,000 people. 5 About 10% of ALS cases are familial, and about 15 to 20% of autosomal dominant familial ALS patients have mutations the superoxide dismutase 1 (SOD1) gene. 6 The pathogenesis remains incompletely understood, but several lines of evidence suggest that oxidative stress plays an important role. SOD 1 is an enzyme that plays a role in detoxifying free radicals 7 . In a transgenic mouse model of familial ALS, there is increased oxidative stress. 8 In patients with sporadic ALS, oxidative stress indicators were found in plasma, urine, and CSF. 9-13 Mitochondrial impairment in ALS is supported by several findings in vitro, animal studies, and patients. In an ALS cell culture model, motor neuron cell lines harboring SOD1 mutations have morphologically abnormal mitochondria and impaired respiratory chain function. 14 Respiratory chain dysfunction has also been described in an ALS mouse model. 15 In spinal cord tissue of ALS patients, mutant mtDNA molecules were incre...