Mitochondria and its role in metabolic regulation and skeletal muscle function in healthy and disease conditions

Skeletal muscle function is critical for our overall health and to be able to perform daily activities. Skeletal muscle has the ability to adapt to various stimuli and mitochondria are known to play an important role in these adaptation processes. Healthy mitochondria are essential for providing skeletal muscle with energy, which are used for various biochemical reactions including generating force and maintaining muscle mass, whereas dysfunctional mitochondria have been associated with loss of skeletal muscle mass and function. In study I, we investigated the role of nuclear-encoded mitochondrial protein NDUFA4L2 in skeletal muscle. NDUFA4L2 has been shown to decrease oxidative phosphorylation and the production of reactive oxygen species in various tissues and cell lines. We ectopically expressed NDUFA4L2 in mouse skeletal muscles with adenovirus-mediated expression and in vivo electroporation. We found that ectopic NDUFA4L2 expression in skeletal muscle reduced mitochondrial respiration and reactive oxygen species production, together with lowered levels of AMP, ADP, ATP, and NAD+, while the overall protein content of mitochondrial remained unchanged. Furthermore, ectopic expression of NDUFA4L2 resulted in smaller muscle mass and hence weaker muscles. The loss of muscle mass was associated with the activation of atrogenes MurF1 and Mul1, and apoptotic genes caspase 3. We used unilateral femoral artery ligation (FAL) as a mouse model of peripheral vascular disease (PVD) to induce muscle ischemia. Our results showed that NDUFA4L2 was induced in skeletal muscle after FAL. The gene expression of Ndufa4l2 correlated with the reduced capacity of the muscle to produce force. In study II, we aim to study the role of mitochondria in PVD-induced muscle dysfunction. PVD lowers blood flow to the lower limbs, causing debilitating skeletal muscle myopathy. Interventions that improve distal arterial pressures (i.e., bypass surgery) generally fail to normalize the functional performance of muscle indicating pathophysiological mechanisms inside the skeletal myofibers that reduce overall muscle function. We performed FAL surgery on mice that were fed either a normal chow diet (ND) or a high-fat diet (HFD) for eight weeks. Our results showed that the muscle weakness induced by FAL was exacerbated in mice fed HFD, together with more serious fibrosis and ectopic fat accumulation in these muscles. Our RNA-sequencing results showed that mitochondrial gene expressions had synchronized reduction in ND-FAL legs, while the reduction was attenuated in HFD-FAL legs. Mitochondrial assembly and cellular respiration were identified as the top suppressed pathway in ND-FAL legs, but not in HFD mice. Fibrosis, fat metabolism, and myosin heavy chain isotypes were amongst the top variable genes in control and FAL muscle from normal and obese mice. Inference of proportions of different cell types with ImmuCC found that HFD has already induced an inflammatory response in skeletal muscle without FAL. Our results suggested that mitochondria content and function may be potential targets to improve muscle function in PVD associated with T2D. Insulin resistance and defects in mitochondrial oxidative phosphorylation (OXPHOS) have been suggested to play an important role in the metabolic dysfunction and muscle impairments caused by T2D. However, we are currently lacking effective treatment against muscle dysfunction in T2D. In study III, we manipulated the mitochondrial electron transport chain (ETC) with our novel NDUFA4L2 genetically knocked-out mouse model. Skeletal muscle lacking NDUFA4L2 appeared stronger, more fatigue resistant, and exhibited higher capillary density and whole-body glucose clearance. NDUFA4L2 knockout mice showed a different metabolic status compared with wild-type litters. Our results indicated that NDUFA4L2 influences skeletal muscle function and hence may be a novel target for T2D-associated muscle dysfunction. The coactivator PGC-1α1 is pivotal to the regulation of mitochondrial function and content in skeletal muscle. In skeletal muscle after exercise, PGC-1α1 enhanced the expression of kynurenine aminotransferases (Kats), an enzyme that catalyzes the conversion from kynurenine to kynurenic acid. In study IV, we observed that PGC-1α1 increased the expression of genes associated with glycolysis and malate-aspartate shuttle (MAS), together with an elevation in aspartate and glutamate levels. These processes promote energy utilization and facilitate the transfer of electrons from the donors to mitochondrial respiration. Thus, trained skeletal muscle can use kynurenine metabolism to increase the bioenergetic efficiency of glucose oxidation through this PGC-1α1-dependent mechanism. Inhibition of Kat with carbidopa resulted in impairments in aspartate biosynthesis, mitochondrial respiration, and skeletal muscle function. After all, the activate MAS and kynurenine catabolism in skeletal muscle after exercise by PGC-1α1 is important for the muscle’s adaptation to endurance training. Taken together, these four studies presented in this thesis highlighted the important role of mitochondria in skeletal muscle and the feasibility of targeting mitochondria for the improvement of skeletal muscle function in both healthy and diseased conditions

Dualities of Dynamic Stochastic Higher Spin Vertex Models through Drinfeld Twister

We introduce a new, algebraic method to construct duality functions for integrable dynamic models. This method will be implemented on dynamic stochastic higher spin vertex models, where we prove the duality functions are the $_3\varphi_2$ functions. The method involves using the universal twister of $\mathcal{U}_q(\mathfrak{sl}_2)$, viewed as a quasi--triangular, quasi--$^*$--Hopf algebra. The algebraic method is presented very generally and is expected to produce duality functions for other dynamic integrable models

Orthogonal polynomial duality and unitary symmetries of multi--species ASEP(q,θ)(q,\boldsymbol{\theta}) and higher--spin vertex models via ∗^*--bialgebra structure of higher rank quantum groups

We propose a novel, general method to produce orthogonal polynomial dualities from the $^*$--bialgebra structure of Drinfeld--Jimbo quantum groups. The $^*$--structure allows for the construction of certain \textit{unitary} symmetries, which imply the orthogonality of the duality functions. In the case of the quantum group $\mathcal{U}_q(\mathfrak{gl}_{n+1})$, the result is a nested multivariate $q$--Krawtchouk duality for the $n$--species ASEP$(q,\boldsymbol{\theta})$. The method also applies to other quantized simple Lie algebras and to stochastic vertex models. As a probabilistic application of the duality relation found, we provide the explicit formula of the $q-$shifted factorial moments (namely the $q$-analogue of the Pochhammer symbol) for the two--species $q$--TAZRP (totally asymmetric zero range process)

THE EFFECT OF ARCH-SUPPORTED FUNCTIONAL INSOLES TO AVOID OVERUSED INJURIES DURING RACE WALKING

This study investigates the effectiveness of functional insoles on plantar pressure distribution during race walking in order to reduce the high plantar pressure and force on race walkers, who tend to suffer from overuse injury. A total of 20 male race walkers were recruited as subjects. Each participant completed a race walk with and without functional insoles. Plantar pressure insoles were used to collect plantar pressure data. A two-way analysis of variance with a mixed design was used to determine the difference between the two conditions. Results show that the use of functional insoles reduced the peak pressure and the impulse in the metatarsal heads and heels and thus suggest that functional insoles reduce the overuse injury risks of these parts. The first ground reaction force peak also decreased. This result suggests that functional insoles reduce the risks of foot and leg injuries

BIOMECHANICS AND INJURY RISK FACTORS DURING RACE WALKING

The purpose of this study is to describe the biomechanical characteristics during race walking and identify whether the race walking rules could cause potential injury risks. Fourteen elite race walkers participated in this study. Rs-scan plantar pressure plate and three digital cameras were used to collect data during race walking and normal walking. Paired t-tests were used to detect the differences. The results showed that during race walking, the peak pressures of the lateral heel and medial heel, the displacements of the center of pressure, ankle dorsiflexion, plantarflexion, knee extension, hip adduction, foot eversion, ankle angular velocity, and average horizontal velocity were significantly larger than those during normal walking. The greater heel peak pressure and more ankle eversion may be the injury risks caused by the rules of race walking

The RELIABILITY OF A NEW DEVICE FOR ASSESSING ANKLE JOINT PRORIOCEPTION IN HEALTHY ADULTS

The objective of this study is to evaluate the within-day and between-day reliability of a new device for assessing ankle joint prorioception. Eleven healthy adults, composed of seven males and four females, participated in the study. Each subject completed three sessions, two on the same day and the last one week later. In each session, three successful testing trials for ankle joint plantarflexion, dosiflexion, inversion, and eversion were performed. The mean values in one direction were calculated and analyzed. The within-day ICC values ranged from 0.808 to 0.973. The SEM for the device ranged from 0.118 ° to 0.448 °. The between-day ICC values ranged from 0.628 to 0.884. The SEM ranged from 0.287 °to 0.618 °. The measurements indicate good to excellent reliability of the device

Orthogonal polynomial duality of a two-species asymmetric exclusion process

We examine type D ASEP, a two--species interacting particle system which generalizes the usual asymmetric simple exclusion process. For certain cases of type D ASEP, the process does not give priority for one species over another, even though there is nontrivial interaction between the two species. For those specific cases, we prove that the type D ASEP is self--dual with respect to an independent product of $q$--Krawtchouk polynomials. The type D ASEP was originally constructed in arXiv:2011.13473, using the type D quantum groups $\mathcal{U}_q(\mathfrak{so}_6)$ and $\mathcal{U}_q(\mathfrak{so}_8)$. That paper claimed that certain states needed to be "discarded'' in order to ensure non--negativity. Here, we also provide a more efficient argument for the same claim