Skeletal muscle unweighting: spaceflight and ground-based models.

Long-term manned spaceflight requires that flight crews be exposed to extended periods of unweighting of antigravity skeletal muscles. This exposure will result in adaptations in these muscles that have the potential to debilitate crew members on return to increased gravity environments. Therefore, the development of countermeasures to prevent these unwanted adaptations is an important requirement. The limited access to microgravity environments for the purpose of studying muscle adaptation and evaluating countermeasure programs has necessitated the use of ground-based models to conduct both basic and applied muscle physiology research. In this review, the published results from ground-based models of muscle unweighting are presented and compared with the results from related spaceflight research. The models of skeletal muscle unweighting with a sufficient body of literature included bed rest, cast immobilization, and unilateral lower limb suspension. Comparisons of changes in muscle strength and size between these models in the context of the limited results available from spaceflight suggest that each model may be useful for the investigation of certain aspects of the skeletal muscle unweighting that occur in microgravity.     

Mechanical and electrical adaptation of skeletal muscle to gravitational unloading

The physiological and biochemical properties of limb skeletal muscle have been shown to adapt to variety of experimental conditions. Among these is the microgravity encountered with spaceflight. It is adaptations accompanying skeletal muscle disuse atrophy. Foremost among these changes is a reduction in the force-generating capacity, which is presumably a direct result of decrease in fiber number and diameter. These changes suggest a spaceflight-induced reduction in muscle work capacity. The interesting finding that the reduction of the mechanical tension is not proportional to the reduction of muscle weight, fiber diameter, and concentration of contractile protein suggested that changes of electrical activity might contribute to the reduction of the contraction force in disused muscle. The purpose of our study was to assess the effects of a 7-d "dry" immersion on the contractile properties of the triceps surae muscle.     

Adaptations of skeletal muscle grafts to chronic changes of physical activity

After grafting, many structural and functional characteristics of skeletal muscle change with time until reaching a stable value. For several characteristics, these stable values are less than those observed in control skeletal muscle. Characteristics such as mass and fiber cross-sectional area are influenced by chronic changes in physical activity. The extent of our understanding of the dimensions and mechanisms of activity-induced adaptations of grafts is limited and based solely on experiments with rats. Improvements in mass, protein content, oxidative capacity, and glycogen concentration have been documented with conditioning by running of sufficient intensity and duration. The growth and development of soleus muscle grafts are severely impaired when normal weight-bearing activity is removed. The mass and maximum tension development of grafts are increased with ablation of muscles that function synergistically to the grafts, but are diminished after chronic electrical stimulation. Chronic electrical stimulation does increase oxidative capacity, capillarity, and the resistance to fatigue. Much remains to be learned about the mechanisms by which activity-related adaptations occur in skeletal muscle grafts.     

Skeletal muscle lactate dehydrogenase isozyme alterations in men and women marathon runners

Total lactate dehydrogenase (LD) and LD isozyme activities in gastrocnemius muscle from trained men and women runners were measured in response to the chronic stress of training for a marathon race (42.2 km). Following 9 wk of training, total LD activity in skeletal muscle from men and women runners significantly (P less than 0.02) decreased 2.26 and 2.25 U/mg protein, respectively. However, men's total LD activities were significantly (P less than 0.001) less than the women's both before and after training. Significant (P less than 0.05) increases in LD1 activities in skeletal muscle in men and women runners were also observed after training. No significant correlations were detected between percent fiber type composition in men or women vs. the changes in total LD activity, changes in LD1 activity, maximal O2 consumption or training distance averaged per week after the training period. The biochemical adaptations in skeletal muscle that occurred in the LD isozyme composition in both men and women runners make the runners skeletal muscle appear similar to heart muscle in LD1 and LD2 activities.     

Skeletal muscle reactive oxygen species: A target of good cop/bad cop for exercise and disease

Abstract

Metabolic stresses associated with disease, ageing, and exercise increase the levels of reactive oxygen species (ROS) in skeletal muscle. These ROS have been linked mechanistically to adaptations in skeletal muscle that can be favourable (i.e. in response to exercise) or detrimental (i.e. in response to disease). The magnitude, duration (acute versus chronic), and cellular origin of the ROS are important underlying factors in determining the metabolic perturbations associated with the ROS produced in skeletal muscle. In particular, insulin resistance has been linked to excess ROS production in skeletal muscle mitochondria. A chronic excess of mitochondrial ROS can impair normal insulin signalling pathways and glucose disposal in skeletal muscle. In contrast, ROS produced in skeletal muscle in response to exercise has been linked to beneficial metabolic adaptations including mitochondrial biogenesis and muscle hypertrophy. Moreover, unlike insulin resistance, exercise-induced ROS appears to be primarily of non-mitochondrial origin. The present review summarizes the diverse ROS-targeted metabolic outcomes associated with insulin resistance versus exercise in skeletal muscle, thus, presenting two contrasting perspectives of pathologically harmful versus physiologically beneficial ROS. Here, we discuss the key sites of ROS production during exercise and the effect of ROS in skeletal muscle of people with type 2 diabetes.     

PGC-1α-mediated changes in phospholipid profiles of exercise-trained skeletal muscle

Exercise training influences phospholipid fatty acid composition in skeletal muscle and these changes are associated with physiological phenotypes; however, the molecular mechanism of this influence on compositional changes is poorly understood. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a nuclear receptor coactivator, promotes mitochondrial biogenesis, the fiber-type switch to oxidative fibers, and angiogenesis in skeletal muscle. Because exercise training induces these adaptations, together with increased PGC-1α, PGC-1α may contribute to the exercise-mediated change in phospholipid fatty acid composition. To determine the role of PGC-1α, we performed lipidomic analyses of skeletal muscle from genetically modified mice that overexpress PGC-1α in skeletal muscle or that carry KO alleles of PGC-1α. We found that PGC-1α affected lipid profiles in skeletal muscle and increased several phospholipid species in glycolytic muscle, namely phosphatidylcholine (PC) (18:0/22:6) and phosphatidylethanolamine (PE) (18:0/22:6). We also found that exercise training increased PC (18:0/22:6) and PE (18:0/22:6) in glycolytic muscle and that PGC-1α was required for these alterations. Because phospholipid fatty acid composition influences cell permeability and receptor stability at the cell membrane, these phospholipids may contribute to exercise training-mediated functional changes in the skeletal muscle.     

Fiber type conversion alters inactivation of voltage-dependent sodium currents in murine C2C12 skeletal muscle cells

Each skeletal muscle of the body contains a unique composition of "fast" and "slow" muscle fibers, each of which is specialized for certain challenges. This composition is not static, and the muscle fibers are capable of adapting their molecular composition by altered gene expression (i.e., fiber type conversion). Whereas changes in the expression of contractile proteins and metabolic enzymes in the course of fiber type conversion are well described, little is known about possible adaptations in the electrophysiological properties of skeletal muscle cells. Such adaptations may involve changes in the expression and/or function of ion channels. In this study, we investigated the effects of fast-to-slow fiber type conversion on currents via voltage-gated Na⁺ channels in the C₂C₁₂ murine skeletal muscle cell line. Prolonged treatment of cells with 25 nM of the Ca²⁺ ionophore A-23187 caused a significant shift in myosin heavy chain isoform expression from the fast toward the slow isoform, indicating fast-to-slow fiber type conversion. Moreover, Na⁺ current inactivation was significantly altered. Slow inactivation less strongly inhibited the Na⁺ currents of fast-to-slow fiber type-converted cells. Compared with control cells, the Na⁺ currents of converted cells were more resistant to block by tetrodotoxin, suggesting enhanced relative expression of the cardiac Na⁺ channel isoform Na_v1.5 compared with the skeletal muscle isoform Na_v1.4. These results imply that fast-to-slow fiber type conversion of skeletal muscle cells involves functional adaptation of their electrophysiological properties. muscle plasticity; myosin heavy chain expression; sodium channel expression     

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.     

Free radicals generated by contracting muscle: by-products of metabolism or key regulators of muscle function?

Skeletal muscle fibers generate reactive oxygen species (ROS) at a number of subcellular sites and this generation is increased by contractile activity. Early studies suggested that generation of superoxide as a by-product of mitochondrial oxygen consumption was the major source of muscle ROS generation and that the species produced were inevitably damaging to muscle, but recent data argue against both of these possibilities. Developments in analytical approaches have shown that specific ROS are generated in a controlled manner by skeletal muscle fibers in response to physiological stimuli and play important roles in the physiological adaptations of muscle to contractions. These include optimization of contractile performance and initiation of key adaptive changes in gene expression to the stresses of contractions. These positive benefits of the ROS that are induced by contractile activity contrast starkly with the increasing evidence that ROS-induced degenerative pathways are fundamental to aging processes in skeletal muscle. A fuller understanding of these contrasting roles is recognized to be important in the design of strategies to maintain and optimize skeletal muscle function during exercise and to help prevent the devastating effects of sarcopenia and other muscle-wasting conditions.     

The 5′ adenosine monophosphate-activated protein kinase: Regulating the ebb and flow of cellular energetics

The 5′ adenosine monophosphate-activated protein kinase (AMPK) is a heterotrimeric, evolutionary conserved enzyme which has emerged as a critical regulator of skeletal muscle cellular bioenergetics. AMPK is activated by both chemical (adipokines) and mechanical (stretch, contraction) stimuli leading to metabolic changes within muscle cells that include increased fatty acid oxidation, glucose uptake and glycolysis, as well as the stimulation and regulation of mitochondrial biogenesis. Collectively these acute responses and chronic adaptations act to reduce cellular disturbances, resulting in tighter metabolic control and maintenance of energy homeostasis. This brief review will describe the structure, function and activation of AMPK in skeletal muscle and how this ubiquitous molecule may be a plausible target for the treatment of several lifestyle-related metabolic disorders.     

Effect of contractile activity on rat skeletal muscle beta-adrenoceptor properties

The effect of fiber type and endurance exercise training on skeletal muscle beta-adrenoceptor properties were assessed using a direct radioligand binding technique. Six separate muscles, composed of a variety of different fiber types, were examined in treadmill trained and sedentary rats. In trained animals, sarcolemmal preparations from heart and slow twitch soleus muscle exhibited a significantly greater receptor concentration than membranes from white fast twitch glycolytic fibers of the vastus lateralis. No significant changes were observed between trained and sedentary rat muscle beta-adrenoceptor density (beta max, fmole/mg protein) or affinity (Kd, nM) within each muscle type, despite significantly increased myocardial/body weight ratios and skeletal muscle enzyme adaptations associated with the exercise program. These results suggest that muscle beta-adrenoceptor properties may be influenced in part by the motor nerve innervation to that muscle, and are further discussed with respect to a possible relationship between exercise intensity and receptor regulation.     

Morphological and physiological properties of non-striated muscle from the tunicate, Ciona intestinalis: parallels with vertebrate skeletal muscle

Non-striated muscle from the longitudinal body wall muscle in an adult ascidian (tunicate) is characterized morphologically and physiologically. These muscles are unique among chordate non-striated (i.e. 'smooth') muscles in that they are composed of discrete bundles of several small diameter (4-10 microns) muscle cells (fibers) arranged in parallel functional units. Each bundle is wrapped by a basal lamina, and at least some appear to be directly innervated at a neuromuscular junction similar to an end plate. In these regards, a bundle of Ciona smooth muscle cells is analogous to a skeletal muscle fiber of a vertebrate. This analogy also extends to physiological properties. Ciona muscle generates a rapid all-or-none Ca action potential which gives rise to a brisk twitch with brief latency. These anatomical and physiological adaptations are discussed in terms of the evolution of vertebrate skeletal muscle.     

Smoothelin-like 1 Protein Regulates Myosin Phosphatase-targeting Subunit 1 Expression during Sexual Development and Pregnancy

Pregnancy coordinately alters the contractile properties of both vascular and uterine smooth muscles reducing systemic blood pressure and maintaining uterine relaxation. The precise molecular mechanisms underlying these pregnancy-induced adaptations have yet to be fully defined but are likely to involve changes in the expression of proteins regulating myosin phosphorylation. Here we show that smoothelin like protein 1 (SMTNL1) is a key factor governing sexual development and pregnancy induced adaptations in smooth and striated muscle. A primary target gene of SMTNL1 in these muscles is myosin phosphatase-targeting subunit 1 (MYPT1). Deletion of SMTNL1 increases expression of MYPT1 30–40-fold in neonates and during development expression of both SMTNL1 and MYPT1 increases over 20-fold. Pregnancy also regulates SMTNL1 and MYPT1 expression, and deletion SMTNL1 greatly exaggerates expression of MYPT1 in vascular smooth muscle, producing a profound reduction in force development in response to phenylephrine as well as sensitizing the muscle to acetylcholine. We also show that MYPT1 is expressed in Type2a muscle fibers in mice and humans and its expression is regulated during pregnancy, suggesting unrecognized roles in mediating skeletal muscle plasticity in both species. Our findings define a new conserved pathway in which sexual development and pregnancy mediate smooth and striated muscle adaptations through SMTNL1 and MYPT1.     

Acute exercise remodels promoter methylation in human skeletal muscle

DNA methylation is a covalent biochemical modification controlling chromatin structure and gene expression. Exercise elicits gene expression changes that trigger structural and metabolic adaptations in skeletal muscle. We determined whether DNA methylation plays a role in exercise-induced gene expression. Whole genome methylation was decreased in?skeletal muscle biopsies obtained from healthy sedentary men and women after acute exercise. Exercise induced a dose-dependent expression of PGC-1α, PDK4, and PPAR-δ, together with a marked hypomethylation on each respective promoter. Similarly, promoter methylation of PGC-1α, PDK4, and PPAR-δ was markedly decreased in mouse soleus muscles 45?min after ex?vivo contraction. In L6 myotubes, caffeine exposure induced gene hypomethylation in parallel with an increase in the respective mRNA content. Collectively, our results provide evidence that acute gene activation is associated with a dynamic change in DNA methylation in skeletal muscle and suggest that DNA hypomethylation is an early event in contraction-induced gene activation.