Alterations In Skeletal Muscle Function Research Articles

Consequences of Reduced Troponin-C Calcium Binding Affinity on Slow Skeletal Muscle

We recently reported significant alterations of mouse cardiac function caused by a mutation (D73N) in cardiac troponin C (TnC) that results in reduced calcium affinity (McConnell et al., Front. Striated Mus. Physiol., doi.org/10.3389/fphys.2015.00242). Many of the cardiac alterations resemble the pathophysiology associated with dilated cardiomyopathy. The heart and slow fibers in skeletal muscle normally express the same isoform of TnC. We, therefore, tested whether the contractile properties of the soleus muscle in mice with the same TnC mutation are altered. Intact soleus muscles were isolated from wild type (WT) and heterozygous knock-in (D73N) mice and contractile properties were measured. Peak forces during isometric twitches and tetani, normalized with muscle cross-sectional area, did not differ between WT and D73N muscles. The times to peak twitch force and to one-half relaxation during twitches and tetani were significantly shorter in D73N muscles. There was a significantly greater reduction in force, over a two-minute fatigue test, in D73N muscles. The force/pCa relationship was measured in skinned slow fibers from the soleus of WT and D73N mice. The pCa50 of the force/pCa curve was significantly different between WT and D73N slow fibers (mean ± SEM: 6.47 ± 0.04 and 6.02 ± 0.02, respectively).The results demonstrate that a mutation in TnC that leads to dilated cardiomyopathy can also induce profound alterations in skeletal muscle function, potentially exacerbating the morbidity associated with cardiomyopathy.

Aging alters contractile properties and fiber morphology in pigeon skeletal muscle.

In this study, we tested the hypothesis that skeletal muscle from pigeons would display age-related alterations in isometric force and contractile parameters as well as a shift of the single muscle fiber cross-sectional area (CSA) distribution toward smaller fiber sizes. Maximal force output, twitch contraction durations and the force-frequency relationship were determined in tensor propatagialis pars biceps muscle from young 3-year-old pigeons, middle-aged 18-year-old pigeons, and aged 30-year-old pigeons. The fiber CSA distribution was determined by planimetry from muscle sections stained with hematoxylin and eosin. Maximal force output of twitch and tetanic contractions was greatest in muscles from young pigeons, while the time to peak force of twitch contractions was longest in muscles from aged pigeons. There were no changes in the force-frequency relationship between the age groups. Interestingly, the fiber CSA distribution in aged muscles revealed a greater number of larger sized muscle fibers, which was verified visually in histological images. Middle-aged and aged muscles also displayed a greater amount of slow myosin containing muscle fibers. These data demonstrate that muscles from middle-aged and aged pigeons are susceptible to alterations in contractile properties that are consistent with aging, including lower force production and longer contraction durations. These functional changes were supported by the appearance of slow myosin containing muscle fibers in muscles from middle-aged and aged pigeons. Therefore, the pigeon may represent an appropriate animal model for the study of aging-related alterations in skeletal muscle function and structure.

Free radical-mediated skeletal muscle dysfunction in inflammatory conditions

Loss of functional capacity of skeletal muscle is a major cause of morbidity in patients with a number of acute and chronic clinical disorders, including sepsis, chronic obstructive pulmonary disease, heart failure, uremia, and cancer. Weakness in these patients can manifest as either severe limb muscle weakness (even to the point of virtual paralysis), respiratory muscle weakness requiring mechanical ventilatory support, and/or some combination of these phenomena. While factors such as nutritional deficiency and disuse may contribute to the development of muscle weakness in these conditions, systemic inflammation may be the major factor producing skeletal muscle dysfunction in these disorders. Importantly, studies conducted over the past 15 years indicate that free radical species (superoxide, hydroxyl radicals, nitric oxide, peroxynitrite, and the free radical-derived product hydrogen peroxide) play an key role in modulating inflammation and/or infection-induced alterations in skeletal muscle function. Substantial evidence exists indicating that several free radical species can directly alter contractile protein function, and evidence suggests that free radicals also have important effects on sarcoplasmic reticulum function, on mitochondrial function, and on sarcolemmal integrity. Free radicals also modulate activation of several proteolytic pathways, including proteosomally mediated protein degradation and, at least theoretically, may also influence pathways of protein synthesis. As a result, free radicals appear to play an important role in regulating a number of downstream processes that collectively act to impair muscle function and lead to reductions in muscle strength and mass in inflammatory conditions.

Skeletal muscle endurance and muscle metabolism in patients with chronic heart failure

Alterations in skeletal muscle function are known to contribute to exercise intolerance in patients with chronic heart failure (CHF). To evaluate whether muscle isometric endurance can be objectively measured and whether it is related to skeletal muscle metabolism in CHF. Isometric endurance of the vastus lateralis, measured as time to fatigue (T(F)), was evaluated in 25 patients with CHF (55+/-8 years of age [mean +/- SD]) and 18 healthy subjects (HS) (62+/-6 years of age [mean +/- SD]). Median frequency of surface electromyography was obtained from spectral analysis using a fast Fourier transformation. Citrate synthase (CS), 3-hydroxyacyl-CoA dehydrogenase (HADH), hexokinase (HK) and phosphofructokinase (PFK) activities were determined from the right vastus lateralis muscle. T(F) was lower in CHF patients than in HS (49+/-4 s and 80+/-7 s, respectively; P<0.01). Muscle fatigue was present at the end of the endurance test in both groups (median frequency breakpoint at mid-exercise for both groups [P<0.05]). CS (P<0.01) and HK (P<0.01) activities were lower in CHF patients than in HS, but PFK activity was higher (P<0.05). T(F) correlated significantly with CS (r=0.50), HADH (r=0.42), PFK (r=-0.47) and HK (r=0.41) activities and the PFK/CS ratio (r=-0.39) when both groups were considered, and with HADH (r=0.47) and PFK (r=-0.57) activities for the CHF group alone (all P<0.05). These results suggest that isometric endurance of the vastus lateralis muscle is reduced in patients with CHF and that it is related to a reduced muscle oxidative capacity.

Effects of moderate heart failure and functional overload on rat plantaris muscle.

It is thought that changes in sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) of skeletal muscle contribute to alterations in skeletal muscle function during congestive heart failure (CHF). It is well established that exercise training can improve muscle function. However, it is unclear whether similar adaptations will result from exercise training in a CHF patient. Therefore, the purpose of this study was to determine whether skeletal muscle during moderate CHF adapts to increased activity, utilizing the functional overload (FO) model. Significant increases in plantaris mass of the CHF-FO and sham-FO groups compared with the CHF and control (sham) groups were observed. Ca(2+) uptake rates were significantly elevated in the CHF group compared with all other groups. No differences were detected in Ca(2+) uptake rates between the CHF-FO, sham, and sham-FO groups. Increases in Ca(2+) uptake rates in moderate-CHF rats were not due to changes in SERCA isoform proportions; however, FO may have attenuated the CHF-induced increases through alterations in SERCA isoform expression. Therefore, changes in skeletal muscle Ca(2+) handling during moderate CHF may be due to alterations in regulatory mechanisms, which exercise may override, by possibly altering SERCA isoform expression.

Effect of chronic K+ deficiency on contractile properties of soleus muscle in rats: evidence of sex differences.

1. Alterations in skeletal muscle function of chronically K(+)-depleted male and female rats were investigated in isolated soleus muscles. 2. By 16 weeks K+ deficiency, plasma K+ concentrations in both male and female rats were reduced to approximately 2 mEq/L, which was accompanied by an approximate 50% reduction in muscle K+ content and a marked increase in muscle Na+ content. These changes were similar in both males and females. 3. Plasma creatine phosphokinase activity progressively increased with time in K(+)-depleted male rats, whereas only a slight increase was observed in female rats. 4. Maximum isometric twitch tension (Pt) and tetanic tension (Po) of K(+)-depleted soleus muscles from male rats was markedly suppressed; this was not seen for soleus muscles obtained from female rats. 5. After exposure to insulin in low-K+ solution, the contractile tension of soleus from the K(+)-depleted male rats was suppressed to a greater extent. 6. All alterations in muscle function during chronic K+ depletion were restored to normal after 2 weeks K+ repletion. 7. The results suggest that there is a preponderance for male over female rats in developing alterations in skeletal muscle function during chronic K+ deficiency. The changes may be associated with abnormalities of muscle membrane permeability and cellular function.

The effects of aging and training on skeletal muscle.

Aging results in a gradual loss of muscle function, and there are predictable age-related alterations in skeletal muscle function. The typical adult will lose muscle mass with age; the loss varies according to sex and the level of muscle activity. At the cellular level, muscles loose both cross-sectional area and fiber numbers, with type II muscle fibers being the most affected by aging. Some denervation of fibers may occur. The combination of these factors leads to an increased percentage of type 1 fibers in older adults. Metabolically, the glycolytic enzymes seem to be little affected by aging, but the aerobic enzymes appear to decline with age. Aged skeletal muscle produces less force and there is a general "slowing" of the mechanical characteristics of muscle. However, neither reduced muscle demand nor the subsequent loss of function is inevitable with aging. These losses can be minimized or even reversed with training. Endurance training can improve the aerobic capacity of muscle, and resistance training can improve central nervous system recruitment of muscle and increase muscle mass. Therefore, physical activity throughout life is encouraged to prevent much of the age-related impact on skeletal muscle.