Functional and Structural Adaptations of Skeletal Muscle to Microgravity

Our purpose is to summarize the major effects of space travel on skeletal muscle with particular emphasis on factors that alter function. The primary deleterious changes are muscle atrophy and the associated decline in peak force and power. Studies on both rats and humans demonstrate a rapid loss of cell mass with microgravity. In rats, a reduction in muscle mass of up to 37% was observed within 1 week. For both species, the antigravity soleus muscle showed greater atrophy than the fast-twitch gastrocnemius. However, in the rat, the slow type I fibers atrophied more than the fast type II fibers, while in humans, the fast type II fibers were at least as susceptible to space-induced atrophy as the slow fiber type. Space flight also resulted in a significant decline in peak force. For example, the maximal voluntary contraction of the human plantar flexor muscles declined by 20–48% following 6 months in space, while a 21 % decline in the peak force of the soleus type I fibers was observed after a 17-day shuttle flight. The reduced force can be attributed both to muscle atrophy and to a selective loss of contractile protein. The former was the primary cause because, when force was expressed per cross-sectional area (kNm-2), the human fast type II and slow type I fibers of the soleus showed no change and a 4% decrease in force, respectively. Microgravity has been shown to increase the shortening velocity of the plantar flexors. This increase can be attributed both to an elevated maximal shortening velocity (V0) of the individual slow and fast fibers and to an increased expression of fibers containing fast myosin. Although the cause of the former is unknown, it might result from the selective loss of the thin filament actin and an associated decline in the internal drag during cross-bridge cycling. Despite the increase in fiber V0, peak power of the slow type I fiber was reduced following space flight. The decreased power was a direct result of the reduced force caused by the fiber atrophy. In addition to fiber atrophy and the loss of force and power, weightlessness reduces the ability of the slow soleus to oxidize fats and increases the utilization of muscle glycogen, at least in rats. This substrate change leads to an increased rate of fatigue. Finally, with return to the 1 g environment of earth, rat studies have shown an increased occurrence of eccentric contraction-induced fiber damage. The damage occurs with re-loading and not in-flight, but the etiology has not been established

Effect of Intermittent Weight Bearing on Soleus Fiber Force-velocity-power and Force-pCa Relationships

Rat permeabilized type I soleus fibers displayed a 33% reduction in peak power output and a 36% increase in the free Ca2+ concentration required for one-half maximal activation after 14 days of hindlimb non-weight bearing (NWB). We examined the effectiveness of intermittent weight bearing (IWB; consisting of four 10-min periods of weight bearing/day) as a countermeasure to these functional changes. At peak power output, type I fibers from NWB animals produced 54% less force and shortened at a 56% greater velocity than did type I fibers from control weight-bearing animals while type I fibers from the IWB rats produced 26% more absolute force than did fibers from the NWB group and shortened at a velocity that was only 80% of the NWB group mean. As a result, no difference was observed in the average peak power of fibers from the IWB and NWB animals. Hill plot analysis of force-pCa relationships indicated that fibers from the IWB group required similar levels of free Ca2+ to reach half-maximal activation in comparison to fibers from the weight-bearing group. However, at forces 1) attenuated the NWB-induced reduction in fiber Ca2+ sensitivity but 2) failed to prevent the decline in peak power that occurs during NWB because of opposing effects on fiber force (an increase vs. NWB) and shortening velocity (a decrease vs. NWB)

Peak Force and Maximal Shortening Velocity of Soleus Fibers after Non-Weight-bearing and Resistance Exercise

Widrick, Jeffrey J., and Robert H. Fitts. Peak force and maximal shortening velocity of soleus fibers after non-weight-bearing and resistance exercise. J. Appl. Physiol. 82(1): 189–195, 1997.—This study examined the effectiveness of resistance exercise as a countermeasure to non-weight-bearing-induced alterations in the absolute peak force, normalized peak force (force/fiber cross-sectional area), peak stiffness, and maximal shortening velocity (V o) of single permeabilized type I soleus muscle fibers. Adult rats were subjected to one of the following treatments: normal weight bearing (WB), non-weight bearing (NWB), or NWB with exercise treatments (NWB+Ex). The hindlimbs of the NWB and NWB+Ex rats were suspended for 14 days via tail harnesses. Four times each day, the NWB+Ex rats were removed from suspension and performed 10 climbs (∼15 cm each) up a steep grid with a 500-g mass (∼1.5 times body mass) attached to their tail harness. NWB was associated with significant reductions in type I fiber diameter, absolute force, normalized force, and stiffness. Exercise treatments during NWB attenuated the decline in fiber diameter and absolute force by almost 60% while maintaining normalized force and stiffness at WB levels. Type I fiberV oincreased by 33% with NWB and remained at this elevated level despite the exercise treatments. We conclude that in comparison to intermittent weight bearing only (J. J. Widrick, J. J. Bangart, M. Karhanek, and R. H. Fitts. J. Appl. Physiol. 80: 981–987, 1996), resistance exercise was more effective in attenuating alterations in type I soleus fiber absolute force, normalized force, and stiffness but was less effective in restoring type I fiberV oto WB levels

Patterns of Parent Behavior Related to Childhood Physical and Mental Abuse

The issue of child abuse is a growing concern in society. However, the limited amount of research available on parent–child relationships poses a challenge in terms of developing effective prevention strategies. The aim of the study was to analyze the connection between a parent who is abusive and their child who is being abused. The main objective of the study was to identify if the gender of the parent had a relationship with abusing the child of the same or different gender. Bowen’s family systems theory was used to support the study because of the assumption that family relationships are the fundamental cause of child abuse. Family systems theory, which involves three subsystems and eight concepts, is crucial in understanding child abuse. The study questions aimed to identify any correlations or trends in physical and psychological abuse, based on the gender of the child and the parent. Secondary data from the National Child Abuse and Neglect Data System were used to answer the research questions. A sample size of 84 participants was calculated using α = .05, medium effect size, and a power of 0.80. The inclusion criteria focused on people who had received services from child protective services agencies, including parents and children, abuse, maltreatment, and child relationships. Correlation, multiple regression, and statistical analysis were used for analytical procedures. The results show that if the parent is the father, there is a statistically significant predictor of likelihood of psychological or emotional maltreatment of male child (p \u3c .001) For future research, it is imperative to thoroughly investigate male abusers, the timeline of abuse within the relationship, and the underlying cause of such behavior. Early detection of child abuse can lead to changes in society and positive behavior promotion, altering cultural standards, and providing interventions for positive relationships

Soleus Fiber Force and Maximal Shortening Velocity After Non-Weight Bearing with Intermittent Activity

This study examined the effectiveness of intermittent weight bearing (IWB) as a countermeasure to non-weight-bearing (NWB)-induced alterations in soleus type 1 fiber force (in mN), tension (P(sub o); force per fiber cross-sectional area in kN/sq m), and maximal unloaded shortening velocity (V(sub o), in fiber lengths/s). Adult rats were assigned to one of the following groups: normal weight bearing (WB), 14 days of hindlimb NWB (NWB group), and 14 days of hindlimb NWB with IWB treatments (IWB group). The IWB treatment consisted of four 10-min periods of standing WB each day. Single, chemically permeabilized soleus fiber segments were mounted between a force transducer and position motor and were studied at maximal Ca(2+) activation, after which type 1 fiber myosin heavy-chain composition was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. NWB resulted in a loss in relative soleus mass (-45%), with type 1 fibers displaying reductions in diameter (-28%) and peak isometric force (-55%) and an increase in V(sub o) (+33%). In addition, NWB induced a 16% reduction in type 1 fiber P., a 41% reduction in type 1 fiber peak elastic modulus [E(sub o), defined as ((delta)force/(delta)length x (fiber length/fiber cross-sectional area] and a significant increase in the P(sub o)/E(sub o) ratio. In contrast to NWB, IWB reduced the loss of relative soleus mass (by 22%) and attenuated alterations in type 1 fiber diameter (by 36%), peak force (by 29%), and V(sub o)(by 48%) but had no significant effect on P(sub o), E(sub o) or P(sub o)/E(sub o). These results indicate that a modest restoration of WB activity during 14 days of NWB is sufficient to attenuate type 1 fiber atrophy and to partially restore type 1 peak isometric force and V(sub o) to WB levels. However, the NWB-induced reductions in P(sub o) and E(sub o) which we hypothesize to be due to a decline in the number and stiffness of cross bridges, respectively, are considerably less responsive to this countermeasure treatment

A High Throughput Substrate Binding Assay Reveals Hexachlorophene as an Inhibitor of the ER-resident HSP70 Chaperone GRP78

Glucose-regulated protein 78 (GRP78) is the ER resident 70 kDa heat shock protein 70 (HSP70) and has been hypothesized to be a therapeutic target for various forms of cancer due to its role in mitigating proteotoxic stress in the ER, its elevated expression in some cancers, and the correlation between high levels for GRP78 and a poor prognosis. Herein we report the development and use of a high throughput fluorescence polarization-based peptide binding assay as an initial step toward the discovery and development of GRP78 inhibitors. This assay was used in a pilot screen to discover the anti-infective agent, hexachlorophene, as an inhibitor of GRP78. Through biochemical characterization we show that hexachlorophene is a competitive inhibitor of the GRP78-peptide interaction. Biological investigations showed that this molecule induces the unfolded protein response, induces autophagy, and leads to apoptosis in a colon carcinoma cell model, which is known to be sensitive to GRP78 inhibition

Concurrent muscle and bone deterioration in a murine model of cancer cachexia

Cachexia is defined as an excessive, involuntary loss of fat and lean tissue. We tested the validity of the Lewis lung carcinoma (LLC) as a model of cancer cachexia and examined its effect on the two major lean tissue components, skeletal muscle and bone. LLC cells (0.75 × 106) were injected into the left thigh of C57BL/6 mice. Control mice received an equal volume injection of growth media. Tumors were observed in all LLC-injected animals 21 and 25 days post inoculation. LLC-injected animals showed significant reductions in fat and lean mass despite having the same average daily caloric intake as media-treated mice. Global bone mineral density (BMD) had fallen by 5% and 6% in the LLC animals at 21 and 25 days, respectively, compared to a BMD increase of 5% in the 25-day media-treated animals. Extensor digitorum longus (EDL) muscles (isolated from the noninjected hindlimb) showed earlier and quantitatively greater losses in mass, physiological cross-sectional area (pCSA), and tetanic force compared to soleus muscles from the same hindlimb. By the 25th day post-LLC inoculation, EDL force/pCSA was reduced by 19% versus media treatment. This loss in specific force was not trivial as it accounted for about one-third of the reduction in EDL absolute force at this time point. Muscle strips dissected from the diaphragm of LLC mice also exhibited significant reductions in force/pCSA at day 25. We conclude that LLC is a valid model of cachexia that induces rapid losses in global BMD and in limb and respiratory muscle function

Force-velocity-power and Force-pCa Relationships of Human Soleus Fibers After 17 Days of Bed Rest

Soleus muscle fibers from the rat display a reduction in peak power and Ca2+ sensitivity after hindlimb suspension. To examine human responses to non-weight bearing, we obtained soleus biopsies from eight adult men before and immediately after 17 days of bed rest (BR). Single chemically skinned fibers were mounted between a force transducer and a servo-controlled position motor and activated with maximal (isotonic properties) and/or submaximal (Ca2+ sensitivity) levels of free Ca2+. Gel electrophoresis indicated that all pre- and post-BR fibers expressed type I myosin heavy chain. Post-BR fibers obtained from one subject displayed increases in peak power and Ca2+ sensitivity. In contrast, post-BR fibers obtained from the seven remaining subjects showed an average 11% reduction in peak power (P \u3c 0.05), with each individual displaying a 7–27% reduction in this variable. Post-BR fibers from these subjects were smaller in diameter and produced 21% less force at the shortening velocity associated with peak power. However, the shortening velocity at peak power output was elevated 13% in the post-BR fibers, which partially compensated for their lower force. Post-BR fibers from these same seven subjects also displayed a reduced sensitivity to free Ca2+(P \u3c 0.05). These results indicate that the reduced functional capacity of human lower limb extensor muscles after BR may be in part caused by alterations in the cross-bridge mechanisms of contraction