Perspectives on Exertional Rhabdomyolysis

© 2017, The Author(s). Exertional (exercise-induced) rhabdomyolysis is a potentially life threatening condition that has been the subject of research, intense discussion, and media attention. The causes of rhabdomyolysis are numerous and can include direct muscle injury, unaccustomed exercise, ischemia, extreme temperatures, electrolyte abnormalities, endocrinologic conditions, genetic disorders, autoimmune disorders, infections, drugs, toxins, and venoms. The objective of this article is to review the literature on exertional rhabdomyolysis, identify precipitating factors, and examine the role of the dietary supplement creatine monohydrate. PubMed and SPORTDiscus databases were searched using the terms rhabdomyolysis, muscle damage, creatine, creatine supplementation, creatine monohydrate, and phosphocreatine. Additionally, the references of papers identified through this search were examined for relevant studies. A meta-analysis was not performed. Although the prevalence of rhabdomyolysis is low, instances still occur where exercise is improperly prescribed or used as punishment, or incomplete medical history is taken, and exertional rhabdomyolysis occurs. Creatine monohydrate does not appear to be a precipitating factor for exertional rhabdomyolysis. Healthcare professionals should be able to recognize the basic signs of exertional rhabdomyolysis so prompt treatment can be administered. For the risk of rhabdomyolysis to remain low, exercise testing and prescription must be properly conducted based on professional standards

One Universal Common Endpoint in Mouse Models of Amyotrophic Lateral Sclerosis

There is no consensus among research laboratories around the world on the criteria that define endpoint in studies involving rodent models of amyotrophic lateral sclerosis (ALS). Data from 4 nutrition intervention studies using 162 G93A mice, a model of ALS, were analyzed to determine if differences exist between the following endpoint criteria: CS 4 (functional paralysis of both hindlimbs), CS 4+ (CS 4 in addition to the earliest age of body weight loss, body condition deterioration or righting reflex), and CS 5 (CS 4 plus righting reflex >20 s). The age (d; mean ± SD) at which mice reached endpoint was recorded as the unit of measurement. Mice reached CS 4 at 123.9±10.3 d, CS 4+ at 126.6±9.8 d and CS 5 at 127.6±9.8 d, all significantly different from each other (P<0.001). There was a significant positive correlation between CS 4 and CS 5 (r = 0.95, P<0.001), CS 4 and CS 4+ (r = 0.96, P<0.001), and CS 4+ and CS 5 (r = 0.98, P<0.001), with the Bland-Altman plot showing an acceptable bias between all endpoints. Logrank tests showed that mice reached CS 4 24% and 34% faster than CS 4+ (P = 0.046) and CS 5 (P = 0.006), respectively. Adopting CS 4 as endpoint would spare a mouse an average of 4 days (P<0.001) from further neuromuscular disability and poor quality of life compared to CS 5. Alternatively, CS 5 provides information regarding proprioception and severe motor neuron death, both could be important parameters in establishing the efficacy of specific treatments. Converging ethics and discovery, would adopting CS 4 as endpoint compromise the acquisition of insight about the effects of interventions in animal models of ALS

miRNA in the Regulation of Skeletal Muscle Adaptation to Acute Endurance Exercise in C57Bl/6J Male Mice

MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNA species involved in post-transcriptional gene regulation. In vitro studies have identified a small number of skeletal muscle-specific miRNAs which play a crucial role in myoblast proliferation and differentiation. In skeletal muscle, an acute bout of endurance exercise results in the up-regulation of transcriptional networks that regulate mitochondrial biogenesis, glucose and fatty acid metabolism, and skeletal muscle remodelling. The purpose of this study was to assess the expressional profile of targeted miRNA species following an acute bout of endurance exercise and to determine relationships with previously established endurance exercise responsive transcriptional networks. C57Bl/6J wild-type male mice (N = 7/group) were randomly assigned to either sedentary or forced-endurance exercise (treadmill run @ 15 m/min for 90 min) group. The endurance exercise group was sacrificed three hours following a single bout of exercise. The expression of miR- 181, 1, 133, 23, and 107, all of which have been predicted to regulate transcription factors and co-activators involved in the adaptive response to exercise, was measured in quadriceps femoris muscle. Endurance exercise significantly increased the expression of miR-181, miR-1, and miR-107 by 37%, 40%, and 56%, respectively, and reduced miR-23 expression by 84% (P≤0.05 for all), with no change in miR-133. Importantly, decreased expression of miRNA-23, a putative negative regulator of PGC-1α was consistent with increased expression of PGC-1α mRNA and protein along with several downstream targets of PGC-1α including ALAS, CS, and cytochrome c mRNA. PDK4 protein content remains unaltered despite an increase in its putative negative regulator, miR-107, and PDK4 mRNA expression. mRNA expression of miRNA processing machinery (Drosha, Dicer, and DGCR8) remained unchanged. We conclude that miRNA-mediated post-transcriptional regulation is potentially involved in the complex regulatory networks that govern skeletal muscle adaptation to endurance exercise in C57Bl/6J male mice

Caloric Restriction Shortens Lifespan through an Increase in Lipid Peroxidation, Inflammation and Apoptosis in the G93A Mouse, an Animal Model of ALS

Caloric restriction (CR) extends lifespan through a reduction in oxidative stress, delays the onset of morbidity and prolongs lifespan. We previously reported that long-term CR hastened clinical onset, disease progression and shortened lifespan, while transiently improving motor performance in G93A mice, a model of amyotrophic lateral sclerosis (ALS) that shows increased free radical production. To investigate the long-term CR-induced pathology in G93A mice, we assessed the mitochondrial bioenergetic efficiency and oxidative capacity (CS – citrate synthase content and activity, cytochrome c oxidase - COX activity and protein content of COX subunit- I and IV and UCP3- uncoupling protein 3), oxidative damage (MDA – malondialdehyde and PC – protein carbonyls), antioxidant enzyme capacity (Mn-SOD, Cu/Zn-SOD and catalase), inflammation (TNF-α), stress response (Hsp70) and markers of apoptosis (Bax, Bcl-2, caspase 9, cleaved caspase 9) in their skeletal muscle. At age 40 days, G93A mice were divided into two groups: Ad libitum (AL; n = 14; 7 females) or CR (n = 13; 6 females), with a diet equal to 60% of AL. COX/CS enzyme activity was lower in CR vs. AL male quadriceps (35%), despite a 2.3-fold higher COX-IV/CS protein content. UCP3 was higher in CR vs. AL females only. MnSOD and Cu/Zn-SOD were higher in CR vs. AL mice and CR vs. AL females. MDA was higher (83%) in CR vs. AL red gastrocnemius. Conversely, PC was lower in CR vs. AL red (62%) and white (30%) gastrocnemius. TNF-α was higher (52%) in CR vs. AL mice and Hsp70 was lower (62%) in CR vs. AL quadriceps. Bax was higher in CR vs. AL mice (41%) and CR vs. AL females (52%). Catalase, Bcl-2 and caspases did not differ. We conclude that CR increases lipid peroxidation, inflammation and apoptosis, while decreasing mitochondrial bioenergetic efficiency, protein oxidation and stress response in G93A mice

Substrate utilization during exercise performed with and without glucose ingestion in female and male endurance trained athletes

Compared to males, females oxidize proportionately more fat and less carbohydrate during endurance exercise performed in the fasted state. This study was designed to test the hypothesis that there may also be gender differences in exogenous carbohydrate (CHOexo) oxidation during exercise. Healthy, young males (n = 7) and females (n = 7) each completed 2 exercise trials (90 min cycle ergometry at 60% VO[sub2peak]), 1 week apart. Females were eumenorrheic and were tested in the midfollicular phase of their menstrual cycle. Subjects drank intermittently either 8% CHOexo (1 g glucose &sdot; kg &sdot; h[sup-1]) enriched with U-13C glucose or an artificially sweetened placebo during the trial. Whole-body substrate oxidation was determined from PER, urinary urea excretion, and the ratio of 13C:12C in expired gas during the final 60 min of exercise. During the placebo trial, fat oxidation was higher in females than in males (0.42 &plusmn; 0.07 vs. 0.32 &plusmn; 0.09 g &sdot; min[sup-1] . kg LBM[sup-1] x 10[sup-2]) at 30 min of exercise (p &lt; .05). When averaged over the final 60 min of exercise, the relative proportions of fat, total carbohydrate, and protein were similar between groups. During CHOexo ingestion, both the ratio of 13C: 12C in expired gas (p &lt; .05) and the proportion of energy derived from CHOexo relative to LBM (p &lt; .05) were higher in females compared to males at 75- and 90-min exercise. When averaged over the final 60 min of exercise, the percentage of CHOexo to the total energy contribution tended to be higher in females (14.3 + 1.2%) than in males (11.2 &plusmn; 1.2%; p = .09). The reduction in endogenous CHO oxidation with CHOexo intake was also greater in females (12.9 &plusmn; 3.1%) than in males (5.1 &plusmn; 2.0%; p = .05). Compared to males, females may oxidize a greater relative proportion of CHOexo during endurance exercise which, in turn, may spare more endogenous fuel. Based on these observations, ingested carbohydrate may be a particularly beneficial source of fuel during endurance exercise for females.<br /

A population-based study of dystrophin mutations in Canada

Introduction: We carried out a population-based study of dystrophin mutations in patients followed by members of the Canadian Paediatric Neuromuscular Group (CPNG) over a ten-year period. Objectives: We aimed to describe the changes in diagnostic testing for dystrophinopathy and to determine the frequency of dystrophin mutations from 2000 to 2009. Methods: De-identified data containing the clinical phenotypes, diagnostic methods, and mutational reports from dystrophinopathy patients followed by CPNG centres from January 2000 to December 2009 were analyzed using descriptive statistics. Results: 773 patients had a confirmed diagnosis of dystrophinopathy based on genetic testing (97%), muscle biopsy (2%), or family history (1%). 573 (74%) had complete deletion/duplication analysis of all 79 exons or whole gene sequencing, resulting in 366 (64%) deletions, 64 (11%) duplications, and 143 (25%) point mutations. The percentage of patients who were diagnosed using currently accepted genetic testing methods varied across Canada, with a mean of 63% (SD 23). 246 (43%) mutations involved exons 45 to 53. The top ten deletions (n=147, 26%) were exons 45-47, 45-48, 45, 45-50, 45-55, 51, 45-49, 45-52, 49-50, and 46-47. 169 (29%) mutations involved exons 2 to 20. The most common duplications (n=29, 5.1%) were exons 2, 2-7, 2-17, 3-7, 8-11, 10, 10-11, and 12. Conclusion: This is the most comprehensive report of dystrophin mutations in Canada. Consensus guidelines regarding the diagnostic approach to dystrophinopathy will hopefully reduce the geographical variation in mutation detection rates in the coming decade

IL-6 Induced STAT3 Signalling Is Associated with the Proliferation of Human Muscle Satellite Cells Following Acute Muscle Damage

Although the satellite cell (SC) is a key regulator of muscle growth during development and muscle adaptation following exercise, the regulation of human muscle SC function remains largely unexplored. STAT3 signalling mediated via interleukin-6 (IL-6) has recently come to the forefront as a potential regulator of SC proliferation. The early response of the SC population in human muscle to muscle-lengthening contractions (MLC) as mediated by STAT3 has not been studied.Twelve male subjects (21±2 y; 83±12 kg) performed 300 maximal MLC of the quadriceps femoris at 180°•s(-1) over a 55° range of motion with muscle samples (vastus lateralis) and blood samples (antecubital vein) taken prior to exercise (PRE), 1 hour (T1), 3 hours (T3) and 24 hours (T24) post-exercise. Cytoplasmic and nuclear fractions of muscle biopsies were purified and analyzed for total and phosphorylated STAT3 (p-STAT3) by western blot. p-STAT3 was detected in cytoplasmic fractions across the time course peaking at T24 (p<0.01 vs. PRE). Nuclear total and p-STAT3 were not detected at appreciable levels. However, immunohistochemical analysis revealed a progressive increase in the proportion of SCs expressing p-STAT3 with ∼60% of all SCs positive for p-STAT3 at T24 (p<0.001 vs. PRE). Additionally, cMyc, a STAT3 downstream gene, was significantly up-regulated in SCs at T24 versus PRE (p<0.05). Whole muscle mRNA analysis revealed induction of the STAT3 target genes IL-6, SOCS3, cMyc (peaking at T3, p<0.05), IL-6Rα and GP130 (peaking at T24, p<0.05). In addition, Myf5 mRNA was up-regulated at T24 (p<0.05) with no appreciable change in MRF4 mRNA.We demonstrate that IL-6 induction of STAT3 signaling occurred exclusively in the nuclei of SCs in response to MLC. An increase in the number of cMyc+ SCs indicated that human SCs were induced to proliferate under the control of STAT3 signaling

Safety and physiological effects of two different doses of elosulfase alfa in patients with morquio a syndrome: A randomized, double-blind, pilot study.

The primary treatment outcomes of a phase 2, randomized, double-blind, pilot study evaluating safety, physiological, and pharmacological effects of elosulfase alfa in patients with Morquio A syndrome are herewith presented. Patients aged ≥7 years and able to walk ≥200 m in the 6-min walk test (6MWT) were randomized to elosulfase alfa 2.0 or 4.0 mg/kg/week for 27 weeks. The primary objective was to evaluate the safety of both doses. Secondary objectives were to evaluate effects on endurance (6MWT and 3-min stair climb test [3MSCT]), exercise capacity (cardio-pulmonary exercise test [CPET]), respiratory function, muscle strength, cardiac function, pain, and urine keratan sulfate (uKS) levels, and to determine pharmacokinetic parameters. Twenty-five patients were enrolled (15 randomized to 2.0 mg/kg/week and 10 to 4.0 mg/kg/week). No new or unexpected safety signals were observed. After 24 weeks, there were no improvements versus baseline in the 6MWT, yet numerical improvements were seen in the 3MSCT with 4.0 mg/kg/week. uKS and pharmacokinetic data suggested no linear relationship over the 2.0-4.0 mg/kg dose range. Overall, an abnormal exercise capacity (evaluated in 10 and 5 patients in the 2.0 and 4.0 mg/kg/week groups, respectively), impaired muscle strength, and considerable pain were observed at baseline, and there were trends towards improvements in all domains after treatment. In conclusion, preliminary data of this small study in a Morquio A population with relatively good endurance confirmed the acceptable safety profile of elosulfase alfa and showed a trend of increased exercise capacity and muscle strength and decreased pain

Supplementary Material: PREMATURE EXPRESSION OF AN AGE-ASSOCIATED MUSCLE SENESCENCE PATHWAY IN HIV INFECTION

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