Timothy J. Doherty

Creatine monohydrate enhances strength and body composition in Duchenne muscular dystrophy

Objective: To determine whether creatine monohydrate (CrM) supplementation increases strength and fat-free mass (FFM) in boys with Duchenne muscular dystrophy (DD). Methods: Thirty boys with DD (50% were taking corticosteroids) completed a double-blind, randomized, cross-over trial with 4 months of CrM (about 0.10 g/kg/day), 6-week wash-out, and 4 months of placebo. Measurements were completed of pulmonary function, compound manual muscle and handgrip strength, functional tasks, activity of daily living, body composition, serum creatine kinase and γ-glutamyl transferase activity and creatinine, urinary markers of myofibrillar protein breakdown (3-methylhistidine), DNA oxidative stress (8-hydroxy-2-deoxyguanosine [8-OH-2-dG]), and bone degradation (N-telopeptides). Results: During the CrM treatment phase, there was an increase in handgrip strength in the dominant hand and FFM (p < 0.05), with a trend toward a loss of global muscle strength (p = 0.056) only for the placebo phase, with no improvements in functional tasks or activities of daily living. Corticosteroid use, but not CrM treatment, was associated with a lower 8-OH-2-dG/creatinine (p < 0.05), and CrM treatment was associated with a reduction in N-telopeptides (p < 0.05). Conclusions: Four months of CrM supplementation led to increases in FFM and handgrip strength in the dominant hand and a reduction in a marker of bone breakdown and was well tolerated in children with DD.

CMT1X phenotypes represent loss of GJB1 gene function

Objective: To investigate possible genotype–phenotype correlations and to evaluate the natural history of patients with Charcot–Marie–Tooth disease type 1X (CMT1X). Background: CMT1X is caused by over 260 distinct mutations in the gap junction beta 1 (GJB1) gene, located on the X chromosome, which encodes the gap junction protein connexin 32 (Cx32). The natural history of CMT1X is poorly understood, and it remains unknown whether particular mutations cause more severe neuropathies through abnormal gain-of-function mechanisms. Methods: We evaluated 73 male patients with CMT1X, who each have 1 of 28 different GJB1 mutations predicted to affect nearly all domains of Cx32. Disability was evaluated quantitatively by the CMT Neuropathy Score (CMTNS) as well as by the CMT Symptom Score (CMTSS) and the CMT Examination Score (CMTES), which are both based on the CMTNS. Patients were also evaluated by neurophysiology. Results: In all patients, disability increased with age, and the degree of disability was comparable with that observed in patients with a documented GJB1 deletion. Disability correlated with a loss of motor units as assessed by motor unit number estimates. Conclusions: Taken together, these data suggest that most GJB1 mutations cause neuropathy by a loss of normal connexin 32 function. Therefore, treatment of male patients with Charcot–Marie–Tooth disease type 1X may prove amenable to gene replacement strategies.

Creatine Monohydrate and Conjugated Linoleic Acid Improve Strength and Body Composition Following Resistance Exercise in Older Adults

Aging is associated with lower muscle mass and an increase in body fat. We examined whether creatine monohydrate (CrM) and conjugated linoleic acid (CLA) could enhance strength gains and improve body composition (i.e., increase fat-free mass (FFM); decrease body fat) following resistance exercise training in older adults (>65 y). Men (N = 19) and women (N = 20) completed six months of resistance exercise training with CrM (5g/d)+CLA (6g/d) or placebo with randomized, double blind, allocation. Outcomes included: strength and muscular endurance, functional tasks, body composition (DEXA scan), blood tests (lipids, liver function, CK, glucose, systemic inflammation markers (IL-6, C-reactive protein)), urinary markers of compliance (creatine/creatinine), oxidative stress (8-OH-2dG, 8-isoP) and bone resorption (Ν-telopeptides). Exercise training improved all measurements of functional capacity (P<0.05) and strength (P<0.001), with greater improvement for the CrM+CLA group in most measurements of muscular endurance, isokinetic knee extension strength, FFM, and lower fat mass (P<0.05). Plasma creatinine (P<0.05), but not creatinine clearance, increased for CrM+CLA, with no changes in serum CK activity or liver function tests. Together, this data confirms that supervised resistance exercise training is safe and effective for increasing strength in older adults and that a combination of CrM and CLA can enhance some of the beneficial effects of training over a six-month period. Trial Registration. ClinicalTrials.gov NCT00473902

Prior heavy exercise elevates pyruvate dehydrogenase activity and speeds O2 uptake kinetics during subsequent moderate‐intensity exercise in healthy young adults

The adaptation of pulmonary oxygen uptake during the transition to moderate‐intensity exercise (Mod) is faster following a prior bout of heavy‐intensity exercise. In the present study we examined the activation of pyruvate dehydrogenase (PDHa) during Mod both with and without prior heavy‐intensity exercise. Subjects (n= 9) performed a Mod1–heavy‐intensity–Mod2 exercise protocol preceded by 20 W baseline. Breath‐by‐breath kinetics and near‐infrared spectroscopy‐derived muscle oxygenation were measured continuously, and muscle biopsy samples were taken at specific times during the transition to Mod. In Mod1, PDHa increased from baseline (1.08 ± 0.2 mmol min−1 (kg wet wt)−1) to 30 s (2.05 ± 0.2 mmol min−1 (kg wet wt)−1), with no additional change at 6 min exercise (2.07 ± 0.3 mmol min−1 (kg wet wt)−1). In Mod2, PDHa was already elevated at baseline (1.88 ± 0.3 mmol min−1 (kg wet wt)−1) and was greater than in Mod1, and did not change at 30 s (1.96 ± 0.2 mmol min−1 (kg wet wt)−1) but increased at 6 min exercise (2.70 ± 0.3 mmol min−1 (kg wet wt)−1). The time constant of was lower in Mod2 (19 ± 2 s) than Mod1 (24 ± 3 s). Phosphocreatine (PCr) breakdown from baseline to 30 s was greater (P < 0.05) in Mod1 (13.6 ± 6.7 mmol (kg dry wt)−1) than Mod2 (6.5 ± 6.2 mmol (kg dry wt)−1) but total PCr breakdown was similar between conditions (Mod1, 14.8 ± 7.4 mmol (kg dry wt)−1; Mod2, 20.1 ± 8.0 mmol (kg dry wt)−1). Both oxyhaemoglobin and total haemoglobin were elevated prior to and throughout Mod2 compared with Mod1. In conclusion, the greater PDHa at baseline prior to Mod2 compared with Mod1 may have contributed in part to the faster kinetics in Mod2. That oxyhaemoglobin and total haemoglobin were elevated prior to Mod2 suggests that greater muscle perfusion may also have contributed to the observed faster kinetics. These findings are consistent with metabolic inertia, via delayed activation of PDH, in part limiting the adaptation of pulmonary and muscle O2 consumption during the normal transition to exercise.

Gait Variability Is Associated With Frailty in Community-dwelling Older Adults

BACKGROUND The relationship between frailty and gait characteristics other than velocity has received little attention. Gait variability quantifies the automaticity of gait with greater variability usually indicating an irregular and unstable gait. High gait variability reflects the loss of gait regulation and predicts mobility decline and falls, which may reveal systemic vulnerability. Thus, we hypothesize that high gait variability may be associated with frailty phenotype. METHODS Cross-sectional study including 100 community-dwelling women and men 75 years and older. Frailty was defined using validated phenotypic criteria and two additional frailty indexes that omit gait velocity criterion were used to verify associations between frailty and quantitative gait parameters. Gait was assessed under usual and fast pace using an electronic walkway. RESULTS Frailty phenotype was identified in 20% of the participants and at least one component of frailty was present in 75%. Linear regression models were generated to explore the associations between frailty and gait variability. In the univariate regression model, frailty was associated with higher variability for all the gait parameters of interest. After adjustments, stride time variability under fast gait condition was the most prominent parameter consistently associated with frailty. This association remained significant in two additional frailty indexes that omit gait velocity criterion. CONCLUSION Frailty is associated with low performance in several quantitative gait parameters beyond velocity of which the most prominent is high stride time variability. This finding may help to understand the high risk of falls and mobility decline in people with frailty.

Motor unit number estimation by decomposition-enhanced spike-triggered averaging: control data, test-retest reliability, and contractile level effects

Decomposition‐enhanced spike‐triggered averaging (DE‐STA) has been developed as a method for obtaining a motor unit number estimate (MUNE). We describe the method and report control data for the first dorsal interosseous/adductor pollicis and thenar muscles and reliability in the thenar muscles. Seventeen subjects (ages 20–50 years) took part in the study. The maximum M potential was elicited with supramaximal stimulation of the ulnar or median nerve at the wrist. Surface and intramuscularly detected electromyographic signals were then collected simultaneously during mild to moderate contractions. Decomposition algorithms were used to detect and sort the individual motor unit potential (MUP) occurrences of several concurrently active motor units in the needle‐detected signals. The MUP occurrences were used as triggering sources to estimate their corresponding surface‐detected MUPs (S‐MUPs) using STA. The mean S‐MUP size was calculated and divided into the maximum M‐potential size to derive a MUNE. The MUNE values were consistent with those previously reported with other methods, and thenar MUNEs for the two trials were similar (249 ± 78 and 246 ± 90), with high test–retest reliability (r = 0.94, P < 0.05). DE‐STA thus appears to be a valid and reliable method to obtain MUNEs. Muscle Nerve 29: 693–699, 2004

Decomposition-based quantitative electromyography: effect of force on motor unit potentials and motor unit number estimates

Decomposition‐based quantitative electromyography (DQEMG) allows for the collection of motor unit potentials (MUPs) over a broad range of force levels. Given the size principle of motor unit recruitment, it may be necessary to control for force when using DQEMG for the purpose of deriving a motor unit number estimate (MUNE). Therefore, this study was performed to examine the effect of force on the physiological characteristics of concentric needle‐ and surface‐detected MUPs and the subsequent impact on MUNEs obtained from the first dorsal interosseous (FDI) muscle sampled using DQEMG. Maximum M waves were elicited in 10 subjects with supramaximal stimulation of the ulnar nerve at the wrist. Intramuscular and surface‐detected EMG signals were collected simultaneously during 30‐s voluntary isometric contractions performed at specific percentages of maximal voluntary contraction (MVC). Decomposition algorithms were used to identify needle‐detected MUPs and their individual MU firing times. These MU firing times were used as triggers to extract their corresponding surface‐detected MUPs (S‐MUPs) using spike‐triggered averaging. A mean S‐MUP was then calculated, the size of which was divided into the maximum M‐wave size to derive a MUNE. Increased levels of contraction had a significant effect on needle‐ and surface‐detected MUP size, firing rate, and MUNE. These results suggest that force level is an important factor to consider when performing quantitative EMG, including MUNEs with this method. Muscle Nerve, 2005

The Effect of a Prehabilitation Exercise Program on Quadriceps Strength for Patients Undergoing Total Knee Arthroplasty: A Randomized Controlled Pilot Study

To examine the effect of a 6‐week prehabilitation exercise training program on presurgical quadriceps strength for patients undergoing total knee arthroplasty (TKA).

Creatine monohydrate supplementation does not increase muscle strength, lean body mass, or muscle phosphocreatine in patients with myotonic dystrophy type 1.

Creatine monohydrate (CrM) supplementation may increase strength in some types of muscular dystrophy. A recent study in myotonic muscular dystrophy type 1 (DM1) did not find a significant treatment effect, but measurements of muscle phosphocreatine (PCr) were not performed. We completed a randomized, double‐blind, cross‐over trial using 34 genetically confirmed adult DM1 patients without significant cognitive impairment. Participants received CrM (5 g, ∼0.074 g/kg daily) and a placebo for each 4‐month phase with a 6‐week wash‐out. Spirometry, manual muscle testing, quantitative isometric strength testing of handgrip, foot dorsiflexion, and knee extension, handgrip and foot dorsiflexion endurance, functional tasks, activity of daily living scales, body composition (total, bone, and fat‐free mass), serum creatine kinase activity, serum creatinine concentration and clearance, and liver function tests were completed before and after each intervention, and muscle PCr/β‐adenosine triphosphate (ATP) ratios of the forearm flexor muscles were completed at the end of each phase. CrM supplementation did not increase any of the outcome measurements except for plasma creatinine concentration (but not creatinine clearance). Thus, CrM supplementation at 5 g daily does not have any effects on muscle strength, body composition, or activities of daily living in patients with DM1, perhaps because of a failure of the supplementation to increase muscle PCr/β‐ATP content. Muscle Nerve 29: 51–58, 2004

Contractile properties of human motor units in health, aging, and disease

The primary function of skeletal muscle is to produce force for postural control and movement. Although the contractile properties of the whole muscle are useful functional indicators, they do not accurately reflect the heterogeneity of the constituent motor units (MUs) and their changes in health and disease. However, data on the contractile properties of human MUs, in comparison to other animal species, are relatively sparse. This, in part, is due to greater methodological challenges of in vivo studies of MUs in the human. The purpose of this review is to critically appraise the methods used in humans; to describe the normative data from different muscle groups; to discuss differences between data from healthy humans and other animal species; and, last, to characterize changes of the MU contractile properties in aging, disease, and in response to intervention. Because the spike‐triggered averaging technique can only be used to study the twitch properties, other methods were subsequently developed to measure a wider range of contractile properties. Although there is general agreement between human data and those from other animal species, major differences do exist. Potential reasons for these discrepancies include true biological differences, but differences in the techniques used may also be responsible. Although limited, measurement of MU contractile properties in humans has provided insight into the changes associated with aging and motoneuronal diseases and provides a means of gauging their adaptive capacity for training and immobilization.