Date of Graduation

7-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Kinesiology (PhD)

Degree Level

Graduate

Department

Health, Human Performance and Recreation

Advisor

Nicholas Greene

Committee Member

Tyrone Washington

Second Committee Member

Michael Wiggs

Third Committee Member

Walter Bottje

Keywords

Disuse Atrophy, Hormones, Mitochondria, Muscle, Muscle wasting, Sex, Sexual dimorphisms

Abstract

Skeletal muscle atrophy is a hallmark of many pathologies and is associated with disease prognosis, quality of life, and mortality. Specifically, lack of contractile activity of the muscle can result in disuse-associated atrophy. Disuse-induced atrophy is a common phenomenon in intensive care unit (ICU) patients and significantly impacts patient prognosis and ability to transition of out of intensive care. However, effective therapeutics to mitigate disuse-associated atrophy do not exist, clearly demonstrating the scientific and clinical need to further understand mechanisms contributing to disuse atrophy. In particular, a significant portion of the scientific literature has utilized male models, yet there is increasing evidence that ICU-associated muscle atrophy may affect females more, demonstrating the necessity to investigate myopathies in both sexes. Mitochondrial aberrations have recently been implicated as a potential therapeutic target to mitigate atrophy. However, to my knowledge mitochondrial aberrations and mitochondrially targeted therapeutics for disuse atrophy have not been investigated in both sexes. Therefore, the purpose of this dissertation was to investigate mitochondrial alterations during the development of disuse atrophy and how biological sex influences the rate of muscle pathologies as well as overall mechanisms contributing to muscle atrophy. To accomplish this, I completed a series of studies using a hindlimb unloading model of disuse in male and female mice. For study 1, male and female mice were hindlimb unloaded for 0 hrs, 24 hrs, 48 hrs, 72 hrs, or 168 hrs to induce muscle atrophy, after designated time points hindlimb muscles were harvested for measures of mitochondrial quality. I find males exhibit mitochondrial stress before the onset of disuse atrophy, whereas females protect mitochondrial quality during disuse atrophy. Yet, females appear to experience disuse atrophy faster compared to males. In study 2, I utilized two separate strains of mice that targeted different components of mitochondrial quality. One strain of mice overexpressed the transcriptional coactivator PGC1α, resulting in increased mitochondrial content. The other strain of mice overexpressed mitochondrially-targeted catalase gene (MCAT). Male and female mice of both strains were hindlimb unloaded for 168 hrs to induce disuse atrophy. While neither intervention mitigated muscle loss in male mice, MCAT females appeared to alleviate muscle loss compared to their WT counterparts, particularly in the atrophy-prone soleus muscle. In study 3 I investigated the potential influence of sex hormones on the development of muscle atrophy. C2C12 myotubes were treated with various atrophic stimuli and incubated with physiological concentrations of testosterone, estrogen, progesterone or estrogen combined with progesterone. Overall, sex hormones appear protective against atrophic stimuli; however the degree of protection and mechanisms contributing to protections vary depending on the atrophic stimulus. More so, estrogen and progesterone can have opposite effects on cellular signaling cascades, depending on the atrophic stimulus. Taken together, this dissertation provides evidence for sex-mediated differences in the progression and development of disuse muscle atrophy and clearly demonstrates the need to investigate myopathies and potential muscle therapeutics in male and female organisms; clearly it is time for more muscle biologists to start “talk[ing] about sex”.

Available for download on Thursday, June 23, 2022

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