الفهرس 
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Abstract
Aging is associated with progressive and irreversible changes in the muscular mass and structure, resulting in decline of muscle strength and function, which is known as sarcopenia that affecting life’s quality. To further clarify the mechanisms that initiate the sarcopenia and its progress, the gastrocnemius and the left ventricle muscles of young (3-4 months), early-aged (10-12 months), and old-aged (22-24 months) female wild-type mice were examined for morphological, behavioral, functional, molecular, and morphometrical analysis.
As shown by magnetic resonance imaging, aging was associated with a reduction in the muscular area of the leg as well as thickening of the left ventricular wall. Behavioral analysis and lactate spectroscopy revealed age-mediated declines in the total distance moved, mean speed, and exhaustion time, with a gradual decrease in the amount of lactate produced.
The results provided evidence that aged mice had significant changes on skeletal and cardiac muscles structure, began with the reduction in the ratio of gastrocnemius muscle weight and heart weight to body weight. Moreover, light microscopy demonstrated an increase of muscle fibers size, with a significant induction of their cross-section area, perimeter, and diameter of both type I and type II muscle fibers, and a reduction in the percentage of muscle area occupied by type II fibers. These changes were accompanied by a decline of fibers number. Enhanced connective tissue infiltrations, and the presence of centrally nucleated muscle fibers, were also found in aged skeletal muscles.
Furthermore, electron microscopy reported age-associated alterations in skeletal muscles that support contractile function loss with age; among them, increased length of sarcomeres, reduction of the overlapped actin/myosin length, excessive collagen accumulation, damaged mitochondria, and formation of multi vesicular bodies. Mitochondrial number increased in the early stage of aging, and reduced lately with increased mitochondrial area. Tubular aggregates were detected in the old-aged skeletal muscles. Their structure confirmed implication of both mitochondria and sarcoplasmic reticulum. Some of these aggregates showed active process of autophagy.
Aging of cardiac muscles as shown by light microscopy was accompanied by necrosis, lymphocytic infiltrations, fibrosis, nuclear splitting, and hypertrophy of the cardiac fibers. Electron microscopy of the old-aged muscles showed presence of multi vesicular bodies, damaged mitochondria, connective tissues accumulation, and appearance of a thick electron-dense membrane around mitochondria. Cardiac muscles aging induced an early significant increase in the number of subsarcolemmal mitochondria, while that of in termyofibrillar showed no significant change. This change was followed by a decline in the old-aged animals. Aged cardiac fibers were also associated with a significant increase in the mitochondrial area.
Mitochondrial respiration experiments on skeletal and cardiac muscles confirmed the strong relation between mitochondrial morphology and function. Aging was associated with declines in the basal respiration, electron transfer system capacity, respiratory control ratio, and adenosine triphosphate production, while proton leak revealed an increase in the aged muscles.
The present study confirmed the mitochondrial theory of aging, as the accumulation of the free radicals released from damaged mitochondria in the aged skeletal and cardiac muscles induced the in flamma some activation that resulted in increased level of the pro-inflammatory mediators, higher expression of the immune responses, and ultimately induction of cellular injury.
Mitochondria were implicated in apoptosis process. As a result of mitochondrial outer membrane permeabilization, damaged mitochondria released apoptosis-initial markers in the cytosol forming apoptosome, which activated a cascade of caspases that initiated DNA damage, nuclear structure disruption, and finally destroying the cell. Also, aging of skeletal and cardiac muscles elucidated increased gene expression and protein content of the pro-apoptotic protein and apoptosis-inducing factor, while those of the anti-apoptotic protein decreased with age.
Autophagic process in both skeletal and cardiac muscles was altered as well by aging. The gene expression and protein content of the autophagic proteins revealed an increase in the early-aged animals. In the old-aged mice, there were marked declines of these proteins.
from altogether, it seems apparent from the present findings that, gastrocnemius and left ventricular muscles of mice display age-related morphological, ultrastructural, functional, and molecular changes, which are implicated in the onset of sarcopenia at the early stage of aging, and its progress at the late stage, with age-mediated activation of inflammasome, apoptosis, and decline of autophagy process.