The role of intracellular calcium perturbations in muscle damage and dysfunction in mouse models of muscular dystrophy

Duchenne muscular dystrophy (DMD) is a neuromuscular disease caused by mutations in the dystrophin gene. DMD is clinically characterized by severe, progressive and irreversible loss of muscle function, in which most patients lose the ability to walk by their early teens and die by their early 20’s. Impaired intracellular calcium (Ca2+) regulation and activation of cell degradation pathways have been proposed as key contributors to DMD disease progression. This dissertation research consists of three studies investigating the role of intracellular Ca2+ in skeletal muscle dysfunction in different mouse models of DMD. Study one evaluated the role of Ca2+-activated enzymes (proteases) that activate protein degradation in excitation-contraction (E-C) coupling failure following repeated contractions in mdx and dystrophin-utrophin null (mdx/utr-/-) mice. Single muscle fibers from mdx/utr-/- mice had greater E-C coupling failure following repeated contractions compared to fibers from mdx mice. Moreover, protease inhibition during these contractions was sufficient to attenuate E-C coupling failure in muscle fibers from both mdx and mdx/utr-/- mice. Study two evaluated the effects of overexpressing the Ca2+ buffering protein sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 1 (SERCA1) in skeletal muscles from mdx and mdx/utr-/- mice. Overall, SERCA1 overexpression decreased muscle damage and protected the muscle from contraction-induced injury in mdx and mdx/utr-/- mice. In study three, the cellular mechanisms underlying the beneficial effects of SERCA1 overexpression in mdx and mdx/utr-/- mice were investigated. SERCA1 overexpression attenuated calpain activation in mdx muscle only, while partially attenuating the degradation of the calpain target desmin in mdx/utr-/- mice. Additionally, SERCA1 overexpression decreased the SERCA-inhibitory protein sarcolipin in mdx muscle but did not alter levels of Ca2+ regulatory proteins (parvalbumin and calsequestrin) in either dystrophic model. Lastly, SERCA1 overexpression blunted the increase in endoplasmic reticulum stress markers Grp78/BiP in mdx mice and C/EBP homologous protein (CHOP) in mdx and mdx/utr-/- mice. Overall, findings from the studies presented in this dissertation provide new insight into the role of Ca2+ in muscle dysfunction and damage in different dystrophic mouse models. Further, these findings support the overall strategy for improving intracellular Ca2+ control for the development of novel therapies for DMD.

Functional Neuroimaging of the Social Regulation of Emotion in Schizophrenia

Negative symptoms in schizophrenia are characterized by deficits in normative experiences and expression of emotion. Social anhedonia (diminished pleasure from social experiences) is one negative symptom that may impact patients’ motivation to engage in meaningful social relationships. Past research has begun to examine the mechanisms that underlie social anhedonia, but it is unclear how this lack of social interest may impact the typically positive effects of social buffering and social baseline theory whereby social support attenuates stress. The present pilot study examines how social affiliation through hand holding is related to subjective and neural threat processing, negative symptoms, and social functioning. Twenty-one participants (14 controls; 7 schizophrenia) developed social affiliation with a member of the research staff who served as the supportive partner during the threat task. Participants displayed greater subjective benefit to holding the hand of their partner during times of stress relative to being alone or with an anonymous experimenter, as indicated by self-reported increased positive valence and decreased arousal ratings. When examining the effects of group, hand holding, and their interaction on the neurological experience of threat during the fMRI task, the results were not significant. However, exploratory analyses identified preliminary data suggesting that controls experienced small relative increases in BOLD signal to threat when alone compared to being with the anonymous experimenter or their partner, whereas the schizophrenia group results indicated subtle relative decreases in BOLD signal to threat when alone compared to either of the hand holding conditions. Additionally, within the schizophrenia group, more positive valence in the partner condition was associated with less severe negative symptoms, better social functioning, and more social affiliation, whereas less arousal was correlated with more social affiliation. Our pilot study offers initial insights about the difficulties of building and using social affiliation and support through hand holding with individuals with schizophrenia during times of stress. Further research is necessary to clarify which types of support may be more or less beneficial to individuals with schizophrenia who may experience social anhedonia or paranoia with others that may challenge the otherwise positive effects of social buffering and maintaining a social baseline.

When Love Becomes Hate(?): The Interplay Between Consumer-Brand Relationships and Crisis Situations

This study had three purposes. First, it aimed to re-conceptualize organization-public relationships (OPRs) in public relations and crisis communication. This OPR re-conceptualization helps find out when the OPR buffering effect or the OPR love-becomes-hate effect happens. Second, it aimed to examine how consumer emotions are influenced by OPRs and influence consumer behavioral intentions. Third, it aimed to address the current problematic operationalization of the concept of consumer. Three pilot studies and one main study were conducted. Apple and Whole Foods were the two brands examined. One crisis that undermined the self-defining attributes shared between the brand and its consumers and another crisis that did not were examined for each brand. Almost 500 Apple consumers and 400 Whole Foods consumers provided usable questionnaires. This study had several major findings. First, non-identifying relationship and identifying relationship were different constructs. Moreover, trust, satisfaction, and commitment were not conceptually separate dimensions of OPRs. Second, the non-identifying relationships offered buffering effects by increasing positive attitudes and tempering anger and disappointment. The identifying relationships primarily offered the love-becomes-hate effects by increasing anger and disappointment. Third, if the crisis was relevant to consumers’ daily lives, brand response strategies were less effective at mitigating consumer negative reactions. Moreover, apology-compensation-reminder strategy was more effective compared to no-comment strategy. However, the apology-compensation-reminder strategy was no more effective than other strategies as long as brands compensate to the victims. Identifying relationships increased the effectiveness of response strategies. If the crisis did not undermine the self-defining attributes shared between consumers and brands, the response strategies worked even better. This study contributes to crisis communication research in multiple ways. First, it advances the OPR conceptualization by demonstrating that non-identifying relationship and identifying relationship are different concepts. More importantly, it advances the theory building of OPRs’ influences on crises by finding out when the buffering effect and the love-becomes-hate effect happen. Second, it adds to emotion research by demonstrating that strong OPRs can lead to negative emotions and positive emotions can have negative behavioral consequences on organizations. Third, the precise operationalization of the concept of consumer gives more insights about consumer reactions to crises.