Jay R. MacDonald

A randomized, controlled trial of creatine monohydrate in patients with mitochondrial cytopathies

Fatigue in patients with mitochondrial cytopathies is associated with decreased basal and postactivity muscle phosphocreatine (PCr). Creatine monohydrate supplementation has been shown to increase muscle PCr and high‐intensity power output in healthy subjects. We studied the effects of creatine monohydrate administration (5 g PO b.i.d. × 14 days → 2 g PO b.i.d. × 7 days) in 7 mitochondrial cytopathy patients using a randomized, crossover design. Measurements included: activities of daily living (visual analog scale); ischemic isometric handgrip strength (1 min); basal and postischemic exercise lactate; evoked and voluntary contraction strength of the dorsiflexors; nonischemic, isometric, dorsiflexion torque (NIDFT, 2 min); and aerobic cycle ergometry with pre‐ and post‐lactate measurements. Creatine treatment resulted in significantly (P < 0.05) increased handgrip strength, NIDFT, and postexercise lactate, with no changes in the other measured variables. We concluded that creatine monohydrate increased the strength of high‐intensity anaerobic and aerobic type activities in patients with mitochondrial cytopathies but had no apparent effects upon lower intensity aerobic activities.

Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders

Mitochondrial disorders share common cellular consequences: (1) decreased ATP production; (2) increased reliance on alternative anaerobic energy sources; and (3) increased production of reactive oxygen species. The purpose of the present study was to determine the effect of a combination therapy (creatine monohydrate, coenzyme Q10, and lipoic acid to target the above‐mentioned cellular consequences) on several outcome variables using a randomized, double‐blind, placebo‐controlled, crossover study design in patients with mitochondrial cytopathies. Three patients had mitochondrial encephalopathy, lactic acidosis, and stroke‐like episodes (MELAS), four had mitochondrial DNA deletions (three patients with chronic progressive external ophthalmoplegia and one with Kearns–Sayre syndrome), and nine had a variety of other mitochondrial diseases not falling into the two former groups. The combination therapy resulted in lower resting plasma lactate and urinary 8‐isoprostanes, as well as attenuation of the decline in peak ankle dorsiflexion strength in all patient groups, whereas higher fat‐free mass was observed only in the MELAS group. Together, these results suggest that combination therapies targeting multiple final common pathways of mitochondrial dysfunction favorably influence surrogate markers of cellular energy dysfunction. Future studies with larger sample sizes in relatively homogeneous groups will be required to determine whether such combination therapies influence function and quality of life. Muscle Nerve, 2006

Acute creatine loading increases fat-free mass, but does not affect blood pressure, plasma creatinine, or CK activity in men and women

UNLABELLED Creatine monohydrate (CrM) administration may enhance high intensity exercise performance and increase body mass, yet few studies have examined for potential adverse effects, and no studies have directly considered potential gender differences. PURPOSE The purpose of this study was to examine the effect of acute creatine supplementation upon total and lean mass and to determine potential side effects in both men and women. METHODS The effect of acute CrM (20 g x d(-1) x 5 d) administration upon systolic, diastolic, and mean BP, plasma creatinine, plasma CK activity, and body composition was examined in 15 men and 15 women in a randomized, double-blind experiment. Additionally, ischemic isometric handgrip strength was measured before and after CrM or placebo (PL). RESULTS CrM did not affect blood pressure, plasma creatinine, estimated creatinine clearance, plasma CK activity, or handgrip strength (P > 0.05). In contrast, CrM significantly increased fat-free mass (FFM) and total body mass (P < 0.05) as compared with PL, with no changes in body fat. The observed mass changes were greater for men versus women. CONCLUSIONS These findings suggest that acute CrM administration does not affect blood pressure, renal function, or plasma CK activity, but increases FFM. The effect of CrM upon FFM may be greater in men as compared with that in women.

Hypotension following mild bouts of resistance exercise and submaximal dynamic exercise

Abstract Our purposes were (1) to examine resting arterial blood pressure following an acute bout of resistance exercise and submaximal dynamic exercise, (2) to examine the effects of these exercises on the plasma concentrations of atrial natriuretic peptide ([ANP]), and (3) to evaluate the potential relationship between [ANP] and post-exercise blood pressure. Thirteen males [24.3 ± (2.4) years] performed 15 min of unilateral leg press exercise (65% of their one-repetition maximum) and, 1 week later, ≈15 min of cycle ergometry (at 65% of their maximum oxygen consumption). Intra-arterial pressure was monitored during exercise and for 1 h post-exercise. Arterial blood was drawn at rest, during exercise and at intervals up to 60 min post-exercise for analysis of haematocrit and [αANP]. No differences occurred in blood pressure between trials, but significant decrements occurred following exercise in both trials. Systolic pressure was ≈20 mmHg lower than before exercise after 10 min, and mean pressure was ≈7 mmHg lower from 30 min onwards. Only slight (non-significant) elevations in [αANP] were detected immediately following exercise, with the concentrations declining to pre-exercise values by 5 min post-exercise. We conclude that post-exercise hypotension occurs following acute bouts of either resistance or submaximal dynamic exercise and, in this investigation, that this decreased blood pressure was not directly related to the release of αANP.

Naproxen does not alter indices of muscle damage in resistance-exercise trained men

PURPOSE Unaccustomed exercise is associated with an elevated plasma creatine kinase (CK), myofibrillar inflammation, and delayed onset muscle soreness (DOMS). Nonsteroidal antiinflammatory drugs (NSAID) may attenuate DOMS and indirect indices of inflammation in humans. METHODS We studied the effects of an NSAID (naproxen sodium (500 mg, 2 times a day for 48 h)) taken before and after resistance exercise in eight healthy, moderately trained men in a randomized, double-blind trial. The exercise consisted of unilateral knee concentric/eccentric weight lifting with 6 sets x 10 repetitions at 80-85% of the 1 repetition maximal contraction. Muscle biopsies of each vastus lateralis (EX = exercised/REST = control) were taken 24 h after exercise for immunohistochemical staining of inflammatory cells (leukocyte common antigen). At 24 and 48 h postexercise, we also determined DOMS, plasma CK activity, and knee extensor muscle torque. RESULTS Exercise resulted in an increased CK activity at +24 and +48 h (vs preexercise: P < 0.01), with no treatment effect. There were no treatment effects for any of the measured variables except for a return of voluntary knee extension torque to baseline by +48 h postexercise for NSAID treatment (P < 0.05). CONCLUSIONS NSAID administration did not alter CK rise, muscle force deficit at 24 h postexercise, nor perceived muscle pain. In addition, the increased CK at 24 h postexercise was not associated with an acute myofibrillar inflammatory cell infiltrate in moderately trained men after resistance exercise.

Diagnostic utility of a modified forearm ischemic exercise test and technical issues relevant to exercise testing.

The sensitivity and specificity of a modified forearm ischemic test (FIT) are described in the diagnosis of glycogen storage disease, myoadenylate deaminase deficiency, and mitochondrial disease. FIT and muscle biopsy results were reviewed from 99 patients (glycogen storage disease [GSD], myoadenylate deaminase deficiency [AMPD], mitochondrial disease [MITO], miscellaneous neuromuscular disorders, and controls). The influence of catheter placement and an antecedent sugar bolus were also assessed in healthy young men. The FIT had a sensitivity of 1.00 and a specificity of 1.00 for a diagnosis of GSD, whereas the corresponding values were 1.00 and 0.37 for AMPD deficiency. A baseline lactate of >2.5 mmol/L provided the highest sensitivity (0.62) and specificity (1.00) for MITO disease. A baseline and +1 min sample provided optimal sensitivity and specificity for GSD and AMPD deficiency. Catheter placement in any vein other than the ipsilateral antecubital resulted in attenuated lactate responses (P < 0.0001). A pre‐FIT sugar bolus did not alter the postexercise lactate or ammonia response. Thus, a modified FIT was helpful in the diagnosis of GSD and excluding AMPD deficiency, but not in the diagnosis of MITO disease. Catheter placement is critical to the interpretation of a FIT, whereas pretesting diet is less important. Muscle Nerve 27: 359–366, 2003

Nutritional inadequacy in adults with muscular dystrophy.

Patients with muscular dystrophy may be prone to nutrient deficiency due to mobility limitations or oropharyngeal weakness. Patients with myotonic muscular dystrophy (DM1) may be particularly prone to nutritional deficiencies from associated dysmotility of the entire gastrointestinal tract. We prospectively evaluated nutritional intake, body composition, and muscle strength in adult patients with DM1 (n = 29) and other muscular dystrophies (n = 22) on two occasions separated by ∼6 months. Handgrip was significantly lower and knee extension higher for DM1 compared to other dystrophies, with no between‐group differences in nutritional intakes. Many patients in both groups demonstrated inadequate nutrient intake of protein, energy, vitamins (water and fat soluble), and minerals (calcium and magnesium). Significant correlations were found between measures of strength and certain individual nutrients (e.g., copper and water‐soluble vitamins). These data indicate that a substantial number of adults with muscular dystrophy do not meet current dietary intake recommendations. The potential clinical implications of these findings are discussed. Muscle Nerve, 2005

Nuclear calcium: transfer to and from the cytosol.

Although the cell nucleus is known to control much of cell function, little is known as to the mediator of such function. Recent evidence has suggested that Ca2+ may be responsible for the regulation of many nuclear events. Early investigations have reported that the nucleus may be able to control its calcium function independently of the adjacent cytosol. IP3 and IP4 may act as regulators of nuclear Ca2+ independently or in parallel with the cytosol. This paper examines the current state of knowledge regarding nuclear calcium regulation. Additionally, a model for this regulation is proposed.