CARM1 and skeletal muscle atrophy / Coactivator-associated arginine methyltransferase 1 (CARM1) is emerging as an important player in skeletal muscle biology. We sought to elucidate the role of CARM1 in mediating muscle mass and function, as well as in the induction and progression of the muscle atrophy program. To this end, we engineered CARM1 skeletal muscle-specific knockout (mKO) mice and employed distinct, but complementary models of muscle atrophy, including neurogenic muscle disuse, food deprivation, and the sarcopenia of aging. CARM1 mKO resulted in reduced muscle mass and myofiber cross-sectional area concomitant with dysregulated autophagic and atrophic signaling, which indicates the requirement of CARM1 for the maintenance of muscle biology. Interestingly, CARM1 deletion mitigated the progression of both denervation- and fasting-induced skeletal muscle atrophy as compared to wild-type (WT) mice. Key mechanistic findings revealed that CARM1 interacts with the master neuromuscular regulator AMPK and attenuates the expression and activity of its downstream autophagy and atrophy networks. Surprisingly, both male and female mKO mice have a significantly shorter lifespan versus their WT littermates, revealed by a ~50% reduction in survival at 22-months-old, which is equivalent to ~70 years-old in humans. As such, we observed significantly reduced functional outcomes of integrative physiology in old mKO mice compared to old WT animals, such as strength and motor performance. Taken together, these results indicate that skeletal muscle CARM1 is indispensable for maintaining muscle mass, function, and lifespan. Targeting the interplay between CARM1 and AMPK may offer a viable therapeutic strategy for combating life-limiting muscle wasting conditions. / Thesis / Doctor of Philosophy (PhD) / While muscle wasting and weakness remains a widespread issue, the mechanisms that control muscle atrophy are not entirely understood. Previous evidence suggests that coactivator-associated arginine methyltransferase 1 (CARM1) regulates skeletal muscle remodeling. However, the role of CARM1 during muscle atrophy is unknown. Therefore, the purpose of this work was to investigate the function of CARM1 during muscle wasting. We generated mice with CARM1 deleted in skeletal muscle and studied the impact of CARM1 deficiency on the loss of skeletal muscle mass during muscle disuse, food deprivation, and aging. We found that CARM1 is required to maintain muscle mass under basal conditions. Interestingly, knocking out CARM1 in muscle attenuated the progression of denervation- and fasting-induced atrophy. However, CARM1 deletion in muscle resulted in lower muscle strength and a reduced lifespan. CARM1 deficiency did not prevent aging-induced muscle loss. Overall, these findings advance our understanding of CARM1 in skeletal muscle biology.

Thesis (M.S.)--West Virginia University, 2010. / Title from document title page. Document formatted into pages; contains vii, 72 p. : ill. (some col). Vita. Includes abstract. Includes bibliographical references (p. 63-70).

Thesis (Ph. D.)--University of Missouri--Columbia, 2004. / "December 2004." Typescript. Vita. Includes bibliographical references (leaves 180-210). Also issued on the Internet.

Ophthalmic diseases such as glaucoma are associated with progressive changes in the structure of the optic disc (OD) and parapapillary atrophy (PPA). These structural changes may therefore have relevance to other systemic diseases. The size and location of OD and PPA can be used as registration landmarks for monitoring changes in features of the fundus of the eye. Retinal vessel evaluation, for example, can be used as a biomarker for the effects of multiple systemic diseases, or co-morbidities. This thesis presents the first computer-aided measuring tool that detects and quantifies the progression of PPA automatically on a 2D retinal fundus image in the presence of image noise. An automated segmentation system is described that can detect features of the optic nerve. Three novel approaches are explored that extract the PPA and OD region approximately from a 2D fundus image. The OD region is segmented using (i) a combination of active contour and morphological operations, (ii) a modified Chan-Vese algorithm and (iii) a combination of edge detection and ellipse fitting methods. The PPA region is identified from the presence of bright pixels in the temporal zone of the OD, and segmented using a sequence of techniques, including a modified Chan-Vese approach, thresholding, scanning filter and multi-seed region growing methods. The work demonstrates for the first time how the OD and PPA regions can be identified and quantified from 2D fundus images using a standard fundus camera.

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Disuse of a limb has been repeatedly demonstrated to cause pronounced atrophy of skeletal muscle. In animals and humans, disuse of a leg due to immobilization can cause pronounced catabolism of many skeletal muscle proteins. Strength, V02 max, oxidative enzyme activities, protein synthesis, and muscle weight are all diminished due to chronic limb immobilization.Testosterone is classified as an anabolic steroid which has the effect of increasing protein synthesis in many tissues. Recently, testosterone has been shown to have a definite anti-catabolic effect on skeletal muacle by competing with glucocorticoids for binding proteins within the muscle cell. This reduces the effect of the circulating catabolic hormones. By slowing protein breakdown and increasing protein synthesis in the skeletal muscle of an immobilized limb, testosterone could effectively delay the rapid atrophy so often seen.To examine the effects of testosterone on skeletal muscle atrophy during limb immobilization, forty albino, male rats were randomly divided into four groups of ten. Group I served as the non-immobilized control and received daily placebo injections of sesame oil. The rats in group II were castrated and their hindlimbs were immobilized using a plaster cast. The animals in this group also received daily injections of sesame oil. The group III rats were also castrated and casted, but they received a daily injection of 5 mg testosterone propionate. The animals in group IV were not castrated but were casted.These rats also received a daily injection of testosterone. The duration of treatment was two weeks for each rat. Body weights were measured before and after treatment. The gastrocnemius, quadriceps, soleus, and cardiac muscles were weighed after treatment. Oxygen consumption capacity (Q02), citrate synthase activity, total protein, and percentage of water were also measured in the gastrocnemius, quadriceps, and cardiac tissues.The results of this study demonstrate that hindlimb immobilization not only causes severe atrophy in those muscles immobilized, but has an overal catabolic effect on the animal. Along with the effects on muscle and body size, the immobilization also significantly reduced the aerobic capacity of affected muscle groups and cardiac tissue. The study also gave evidence that testosterone, or the lack of it, can affect the rate of muscle atrophy. The greatest reduction in body weight, muscle size, heart size, and QO2 were seen in the castrated group which only received a placebo injection of sesame oil. The anti-catabolic effect of testosterone was evedent in groups III and IV.

The Effects of a glucocorticoid-antagonist on IGF1-stimulated glucose uptake in skeletal muscle of hindlimb suspended rats. Barnes B.R., T.C. Selix, D.C. Wright, and B.W. Craig. Ball State University, Muncie, IN.The purpose of this investigation was to determine the effects of a glucocorticoid-antagonist (RU486) on insulin-like-growth-factor-1 (IGF1)stimulated glucose transport following two weeks of hindlimb suspension (HS) on 100 gm male rats. After two weeks of HS and/or oral RU486 administration the animals were anesthetized, and the soleus (SOL) and extensor digitorum longus (EDL) muscles isolated and clamped at their resting length. Following an incubation series to prepare the muscle, the muscle was incubated in radioactive 3-O-methylglucose for 10 min. in the presence/absence of 75 ng/ml of IGF1, digested with 0.5 NaOH, and the amount of glucose transported measured. Two weeks of RU486 treatment significantly (P:5 0.05) elevated IGF1-stimulated glucose transport of SOL (0.576 ± 0.071 vs 1.405 ± 0.172), whereas the EDL was unaffected (2.728 0.258 vs 2.613 ± 0.182). The removal of glucocorticoids via RU486 administration significantly increased glucose uptake in HS exposed soleus muscles. The EDL was not affected by RU486 treatment. / School of Physical Education

The human androgen receptor (hAR) is a ligand-activated, DNA-binding nuclear transcription factor. Mutations in the hAR result in varying degrees of androgen insensitivity (AI); they may play a predisposing or pathogenetic role in both prostate and breast cancer. Expansion of the hAR's N-terminal polymorphic Glutamine (Gln) repeat causes a late-onset progressive motoneuronopathy which is associated with mild androgen insensitivity: spinal and bulbar muscular atrophy (SBMA). SBMA belongs to a group of translated CAG trinucleotide repeat expansion neuronopathies that includes Huntington disease, dentatorubral-pallidoluysian atrophy and five distinct spinocerebellar ataxias. The fact that this group of disorders is caused by polyGln expansions in totally unrelated proteins, is one of the main reasons for postulating that a common gain-of-function mechanism must underlie their communal pathogenesis. This common pathogenetic mechanism is postulated to occur via aberrant protein interactions. / I undertook a search for hAR-interacting proteins using a yeast two-hybrid system. A human testes cDNA library was screened several times with two forms of an N-terminal fragment of the hAR: a normal (20 Gin) hAR and an expanded (50 Gin) hAR. A few candidate hAR-interacting proteins were isolated during the library screenings and I tested them for physiological relevance. / A second aspect of my project included the analysis of an aberrant 75-kD protein fragment generated in COS-1 cells transfected with a polyCAG-expanded (n = 44) hAR cDNA. Recent work in Huntington disease and spinocerebellar ataxia type 3 shows the accumulation of insoluble protein aggregates primarily in the nucleus of certain brain cells (Davies et al., 1997; Scherzinger et al., 1997; Paulson et al., 1997). I confirmed the presence of the aberrant hAR-fragment in the nucleus through western analysis of protein samples extracted from the nucleus.