Alterations in Skeletal Muscle Plasticity with Smoking, Smoking Cessation and Vitamin D Deficiency in Mice

Tanjeko, A. T. (2020) Alterations in Skeletal Muscle Plasticity with Smoking, Smoking Cessation and Vitamin D Deficiency in Mice. Doctoral thesis (PhD), Manchester Metropolitan University.

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Abstract

Cigarette smoking is a prime cause of morbidity and mortality worldwide. It is a major risk factor for the development of cardiovascular diseases, various cancers, respiratory disorders, and skeletal muscle dysfunction. The adverse effects of cigarette smoking beyond the respiratory system has been an area of rising interest, particularly its impact on skeletal muscles. Considering the capital role of skeletal muscles in movement, maintenance of posture, metabolism, and vital functions such as respiration, a proper understanding of the manifestations and mechanisms of smoking-induced skeletal muscle dysfunction and development of strategies to curb the ensuing morbidities and mortality is necessary. In humans and animal models the manifestations of smoking-induced skeletal muscle dysfunction include: atrophy, weakness, decreased mitochondrial function and bioenergetics, reduced force and fatigue resistance, decreased protein synthesis, increased proteolysis, capillary regression, reduced vasodilation, decreased perfusion, increased inflammation and oxidative stress. Smoking cessation is the most efficient and cheapest way to avert these deleterious alterations in skeletal muscle structure and function as a result of smoking. In fact, long term smoking cessation has been shown to restore whole body and skeletal muscle mass, increase muscle mitochondrial function, and improve muscle plasticity in humans and animal models. However, prior to our study, evidence of short-term (1 to 2 weeks) benefits of smoking cessation were lacking. Our study in mice reveals that smoking cessation for as short as 1 to 2 weeks leads to immediate benefits on the diaphragm and limb muscles demonstrated by the reversal of muscle mass loss, recovery of whole-body fat and especially lean mass, and improvement of mitochondrial function. We also show that the constantly active diaphragm muscle is most affected by cigarette smoking and recovers rapidly after smoking cessation. Considering the fact that the devastating effects of smoking on skeletal muscles occur slowly and may only manifest later in life, these results are important as they could motivate smokers to stop smoking as soon as possible to avoid long term muscle wasting and weakness. The maintenance and improvement of skeletal muscle mass and plasticity is highly recommended, especially for people suffering from muscle wasting such as patients with COPD, cancer, dystrophic muscle diseases, chronic smokers and the elderly in whom smoking and vitamin D deficiency is also prevalent. Skeletal muscle hypertrophy is a normal response of skeletal muscles to resistance training and overload which lead to increased mass and fiber cross-sectional area. It is usually accompanied by beneficial adaptations, such as muscle mitochondrial biogenesis, increased protein anabolism, reduced proteolysis, enhanced vasodilatory capacity and capillary proliferation that are associated with an increased force generating capacity and fatigue resistance of the muscle. However, cigarette smoke may impair the hypertrophic response to overload. Vitamin D plays a vital role in skeletal muscle plasticity and regeneration and vitamin D deficiency, which is highly prevalent worldwide, leads to skeletal muscle dysfunction with similar manifestations to those orchestrated by cigarette smoke such as fiber atrophy, loss of muscle mass and muscle mitochondrial dysfunction. Our second study was therefore designed to understand the impact of smoking alone, vitamin D deficiency alone or a combination of these factors on the skeletal muscle hypertrophic response in mice. Our results showed that smoking or vitamin D deficiency alone did not diminish the hypertrophic response to overload in the plantaris muscles, but this hypertrophic response was attenuated in the presence of both conditions, as indicated by the attenuated fiber hypertrophy in vitamin D-deficient smoking mice. Therefore, a combination of these risk factors impairs the skeletal muscle hypertrophic response. These data are relevant for consideration in the design and implementation of strategies to improve muscle mass, especially in smokers and vitamin D deficient individuals. Our studies report the short-term benefits of smoking cessation that include an improved mitochondrial function and limb muscle mass. This is particularly relevant as an incentive to encourage smoking cessation in smokers and individuals suffering from muscle deterioration yet struggling with smoking cessation. We also show the synergistic deleterious effect of smoking combined with vitamin D deficiency on the skeletal muscle hypertrophic response to overload. This is relevant as it may help in understanding the differences in skeletal muscle response to exercise training and could improve the interventions to restore or improve muscle mass.