Changes in skeletal muscle biochemistry and histology relative to fiber type in rats with heart failure

Abstract

One of the primary consequences of left ventricular dysfunction (LVD) after myocardial infarction is a decrement in exercise capacity. Several factors have been hypothesized to account for this decrement, including alterations in skeletal muscle metabolism and aerobic capacity. The purpose of this study was to determine whether LVD-induced alterations in skeletal muscle enzyme activities, fiber composition, and fiber size are 1) generalized in muscles or specific to muscles composed primarily of a given fiber type and 2) related to the severity of the LVD. Female Wistar rats were divided into three groups: sham-operated controls (n = 13) and rats with moderate (n = 10) and severe (n = 7) LVD. LVD was surgically induced by ligating the left main coronary artery and resulted in elevations (P < 0.05) in left ventricular end-diastolic pressure (sham, 5 +/- 1 mmHg; moderate LVD, 11 +/- 1 mmHg; severe LVD, 25 +/- 1 mmHg). Moderate LVD decreased the activities of phosphofructokinase (PFK) and citrate synthase in one muscle composed of type IIB fibers but did not modify fiber composition or size of any muscle studied. However, severe LVD diminished the activity of enzymes involved in terminal and beta-oxidation in muscles composed primarily of type I fibers, type IIA fibers, and type IIB fibers. In addition, severe LVD induced a reduction in the activity of PFK in type IIB muscle, a 10% reduction in the percentage of type IID/X fibers, and a corresponding increase in the portion of type IIB fibers. Atrophy of type I fibers, type IIA fibers, and/or type IIB fibers occurred in soleus and plantaris muscles of rats with severe LVD. These data indicate that rats with severe LVD after myocardial infarction exhibit 1) decrements in mitochondrial enzyme activities independent of muscle fiber composition, 2) a reduction in PFK activity in type IIB muscle, 3) transformation of type IID/X to type IIB fibers, and 4) atrophy of type I, IIA, and IIB fibers.

Role of the Exercise Pressor Reflex in Rats With Dilated Cardiomyopathy

“…Alterations in skeletal muscle morphology and function, including atrophy, 2,4 changes in fiber type composition, 2,3,25,26 decreased oxidative capacity, 2,25,27,28 abnormal high-energy phosphate handling, 29 and exercise-induced hyperkalemia, 30 have been demonstrated in heart failure. Given these changes, it has been hypothesized that neural reflexes originating within skeletal muscle (ie, the EPR) potentially contribute to the aberrant cardiovascular response to physical activity noted with the pathogenesis of CHF.…”

“…23 If this scenario proves valid, there may be periods of hyperexcitability for both metabolically and mechanically sensitive afferents during the course of heart failure that explain some of the discrepancies reported in previous human studies. 10,14,21,22 In addition, other factors, including modifications in muscle metabolism and fiber type composition (eg, reductions in the percentage of oxidative fibers and increases in the percentage of glycolytic fibers), 2,3,25 may facilitate these disease-induced alterations in reflex function. For example, because the EPR-mediated circulatory response to activation of glycolytic muscle has been shown to be greater than the response elicited from oxidative muscle, 36 fiber-type transformations could profoundly effect the physiological expression of the pressor reflex.…”

“…Muscle atrophy, decreased peripheral blood flow, fiber-type transformation, and reduced oxidative capacity are important factors limiting exercise performance in CHF. [1][2][3][4][5][6] In addition, cardiovascular regulation during physical activity is clearly altered with CHF, because studies using dynamic and static forms of exercise have demonstrated augmentations in sympathetic nerve activity, vascular resistance, heart rate (HR), and blood pressure. [7][8][9][10][11][12][13][14][15] Two distinct neural control mechanisms are activated by exercise: central command and the exercise pressor reflex (EPR).…”

Protein tyrosine nitration in chronic intramuscular parasitism: immunohistochemical evaluation of relationships between nitration, and fiber type-specific responses to infection

“…This response also was observed in studies where subjects with left ventricular dysfunction presented Type IIb-specific fiber atrophy. 11 However, the proinflammatory stress of septicemia as directed through cytokine mediators like TNF-a appears to trigger responses more akin to those we observed here where concomitant with increased proteosomal activity the predominant impact on muscle fiber atrophy was specifically associated with slow oxidative-Type I fibers. 12 The present data are therefore consistent with the concept that cytokine-mediated proinflammatory stress induces selective nitration as well as ubiquitination of proteins directing the involved proteins towards elimination from the cell.…”

“…This intrigued us for two reasons. First, the various fiber types have different metabolic characteristics and mitochondrial densities 9,10 and the mitochondrial response of a given fiber type may predispose that muscle to respond differently to incurred proinflammatory mediators, 11,12 largely because of the propensity of fibers higher in mitochondrial content to generate more nitric oxide (NO) and superoxide anion if perturbed by proinflammatory mediators like tumor necrosis factor-a (TNF-a). Second, proinflammatory excesses of superoxide anion and nitric oxide might satisfy the temporal and spatial requirements needed to generate post-translational chemical protein modifications such as tyrosine nitration, detectable as 3'-nitrotyrosine (NT).…”