The goal of this dissertation was to identify and characterize underlying mechanisms of exercise-induced muscle damage (EIMD) and muscle adaptation to damage. Study I examined contributions of central and peripheral factors to EIMD. Forty-six subjects performed voluntary and stimulated contractions before and immediately following eccentric exercise of the elbow flexors. Subjects demonstrating greater strength loss (a hallmark of EIMD) after eccentric exercise also had greater impairment of peripheral function, but similar central function compared with lower strength loss subjects, suggesting that the mechanism(s) driving variation in strength loss are localized mainly within the periphery. Study II further focused on peripheral factors, specifically molecular changes in gene expression within muscle tissue following eccentric exercise, to determine underlying molecular mechanisms of damage development. Three subjects performed an exercise in which one leg underwent concentric contractions, and the other leg performed both eccentric and concentric actions. Dependent variables included strength loss, soreness and serum creatine kinase activity. Muscle biopsy samples were taken 4-8h post-exercise. Microarray analysis of these samples identified upregulation of genes involved in inflammation, apoptosis (programmed cell death), structure and transcriptional regulation. These results provided the first global gene expression pattern of human muscle after eccentric exercise. EIMD is attenuated naturally via the repeated bout effect, where an initial bout of exercise confers a protective effect on muscle that results in less damage induced by a second bout of exercise. Study III aimed to identify mechanisms driving this adaptation. Seven subjects performed two bouts of eccentric exercise of the leg spaced 4wk apart. Muscle strength and soreness were evaluated and biopsies were collected at 6h post-exercise. Muscle samples were tested for expression of a subset of inflammatory genes identified in Study II. Study III showed upregulation of monocyte chemoattractant protein-1 and the transcription factors CEBPD and ZFP36 following the repeated bout. Monocyte chemoattractant protein 1 (MCP-1) was co-localized to macrophages and satellite cells, which are vital to muscle regeneration. These data suggest that specific alterations in the inflammation response may drive the repeated bout effect, possibly by enhancing communication between macrophages and satellite cells, which may strengthen muscle regeneration following EIMD.

For decades, most scientists and practitioners have agreed that muscle hypertrophy also induces strength gains. However, a recent publication "The Problem of Muscle Hypertrophy: Revisited," questioned the mechanistic role that exercise-induced increases in muscle size have on the exercise-induced increases in strength (of force production), as well as the influence that exercise-induced increases in strength have on sports performance. Such suggestions undermine the important of certain aspects of strength and conditioning for sport. Specifically, if not acting as a mechanism for strength adaptation, it is unclear if there is a sports-related benefit to skeletal muscle hypertrophy. In addition, the authors argued that if strength has little impact on sports performance, strength and conditioning programs may be doing little more than delaying recovery from practicing the actual sport. This contention also indicates that hypertrophy should be avoided in nearly all scenarios because increased muscle size would be additional mass that must be overcome. The purpose of this special discussion is to allow for an in-depth scientific discussion of the experimental evidence for and against the position of Buckner et al. That exercise-induced increases in muscle size have little relevance on the exercise-induced increases in strength and thus, sport performance.

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Eight endurance~trained cyclists rode as far as possible in 1 h on a stationary cyclesimulator in a moderate environment (20°C, 60% relative humidity, 3 m/s wind speed) while randomly receiving either no fluid (NF) or attempting to replace their ~1.7 l sweat loss measured in a previous 1 h familiarisation performance ride at ~85% of peak oxygen uptake (VO₂ peak) with artificially sweetened, coloured water (F). During F the cyclists drank 1.49 ± 0.14 1 (values are mean± SEM), of which 0.27 ± 0.08 1 remained in the stomach at the end of exercise and 0.20 ± 0.05 1 was urinated after the trial. Thus, only 1.02 ± 0.12 l of the ingested fluid was available to replace sweat losses during the 1 h performance ride. That fluid decreased the average heart rate from 166 ± 3 to 157 ± 5 beats/min (P < 0.0001) and reduced the final serum [Na+] and osmolalities from 143 ± 0.6 to 139 ± 0.6 mEq/1 (P < 0.005) and from 294 ± 1.7 to 290 ± 1.9 mOsm/1 (P = 0.05), respectively. Fluid ingestion did not attenuate rises in plasma anti diuretic hormone and angiotensin concentrations, or decrease the ~-15% falls in estimated plasma volume in the F and NF trials. Nor did fluid ingestion significantly effect the ~1.7 l/h sweat rates, the rises in rectal temperature (~36.6° to 38.3°C) or the ratings of perceived exertion in the two trials. Ingestion of ~1.5 l of fluid produced an uncomfortable stomach fullness and reduced the distance covered in 1 h from 43.1 ± 0. 7 to 42.3 ± 0.6 km (P<0.05). Thus, trying to replace > 1.0 l/h sweat losses during high-intensity, short duration exercise in a moderate environment does not induce beneficial physiological effects, and may impair exercise performance.

In this paper, we investigate the potential for the development of a composite score investigating population-level phenotype changes in a mouse model of traumatic brain injury. Traumatic brain injuries (TBI) are a growing concern in the United States because the number of individuals impacted by TBI and associated symptoms is increasing, leading to a growing demand for research both in the clinical and preclinical setting. However, preclinical TBI modeling is complicated by the lack of inter and intra lab consistency in the assessment of behavioral and pathologic outcomes. Indeed, it remains unclear which behavior assessments are most useful in evaluating the effects of preclinical TBI. To investigate the relative contribution of various behavior tests in the assessment of preclinical TBI, three statistical models (simple linear regression, pairwise correlation, and factor analysis) were conducted on behavioral data from the Mannix-Meehan lab at Boston Children’s Hospital in Boston, Massachusetts, U.S.A. from 2012-2018. In this paper, a composite metric was created from the computation analysis of the three statistical methods. The score revealed MWM and EPM as the most potent behavioral tests. The Open Field and Rotarod test had a small impact on the outcome, but only in one of the three statistical models assessed. Thus, to effectively analyze treatment efficiencies, injury severity and long-term impairments, MWM and EPM are the best behavioral test for a mouse model. Furthermore, this method of analysis of entire populations of mice allows for more subtle phenotypic changes resultant from injury models to be revealed, and the generalizability of this model lends to widespread use.

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