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00005768-199610000-0004200005768_1996_28_101_baldwin_plasticity_10miscellaneous-article< 80_0_9_4 >Medicine & Science in Sports & Exercise©1996The American College of Sports MedicineVolume 28(10)October 1996pp 101-106Effects of altered loading states on muscle plasticity: what have we learned from rodents?[International Workshop on Cardiovascular Rearch in Space: Integrated Physiology of μG]BALDWIN, KENNETH M.Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92717Submitted for publication December 1995.Accepted for publication May 1996.This paper was supported in part by NASA NAG2-555 and NIH AR 30346 and HL 38819.Address for correspondence: Kenneth M. Baldwin, Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92717.ABSTRACTThis paper summarizes the key findings concerning the adaptive properties of rodent muscle in response to altered loading states. When the mechanical stress on the muscle is chronically increased, the muscle adapts by hypertrophying its fibers. This response is regulated by processes resulting in contractile protein expression reflecting slower phenotypes, thereby enabling the muscle to better support load-bearing activity. In contrast, reducing the load-bearing activity induces an opposite response whereby muscles used for both antigravity function and locomotion atrophy while transforming some of the slow fibers into faster contractile phenotypes. Accompanying the atrophy is both a reduced power generating and activity sustaining capability. These adaptive processes are regulated by both transcriptional and translational processes. Available evidence further suggests that the interaction of heavy resistance activity and hormonal/growth factors (insulin-like growth factor, growth hormone, glucocorticoids, etc.) are critical in the maintenance of muscle mass and function. Also resistance training, in contrast to other activities such as endurance running, provides a more economical form of stress because less mechanical activity is required to maintain muscle homeostasis in the context of chronic states of weightlessness.The primary goal of this paper is to summarize research concerning the effects of altered loading states on the morphological, functional, and molecular properties of skeletal and cardiac muscle. The discussion will examine both ground-based models and spaceflight missions involving adult rodents whereby the weight-bearing (mechanical) load (or afterload) chronically imposed on the muscle(s) is either sufficiently increased or decreased to induce a change in the amount and type of protein it expresses. Although the discussion will focus primarily on the contractile protein myosin as the marker molecule in which to assess the plasticity of muscle fibers, other organelles involved in both contraction and energy metabolism also will be included. Also, information will be provided as to how altered mechanical stress affects cardiac muscle plasticity.Myosin Expression in Striated MuscleMyosin expression is highly plastic in striated muscles of adult mammals. It is under the control of a multi-gene family encoded for several myosin heavy chain (MHC) isoforms, i.e., molecules with slightly different structural and functional properties (27). In heart muscle, two MHC genes encode for protein isoforms designated as alpha and beta(31) (Fig. 1). The alpha MHC isoform gives rise to a native myosin protein designated as V1. This isoform is known to be fast owing to the high ATPase activity comprising the alpha MHC. Hearts predominately expressing the V1 isoform posses a high intrinsic level of contractility, i.e., intensity of contraction. The V1 isoform is inherently expressed in small animals (e.g., mice and rodents) having a very rapid intrinsic heart rate. In contrast, the beta MHC isoform has low ATPase properties. It forms a slow native myosin called V3, which enables the heart to be more economical in generating pressure and ejecting blood(18). This isoform predominates in the heart cells of larger animals including humans, i.e., species possessing an intrinsically lower maximal heart rate. Interestingly, the beta MHC isoform expressed in cardiac tissue is identical to the slow (Type I) MHC isoform expressed in slow-twitch skeletal muscle fibers spanning all mammalian species.Figure 1-Schematic diagram depicting how the subcellular components of the myosin molecule are assembled into the native protein. The figure depicts the combination of myosin heavy chain and light chain subunits that derive the native isoforms expressed in mammalian cardiac and skeletal muscle. The legend is depicted in the figure.Adult skeletal muscle, in contrast to the heart, is unique in that it expresses three fast MHC isoforms designated as IIa, IIx, and IIb(Fig. 1). This provides skeletal muscle with considerable structural and functional diversity as compared to the heart(27,35), owing to the subtle differences in the energy transduction properties that occur among the skeletal MHC isoforms(27). Thus, this continuum of skeletal MHC isoform expression in mammalian muscle, including humans, enables one to perform a variety of motor activities of varying skill, economy, and power.Plasticity in Response to Altered Loading StatesResponses to functional overload. In rodents when a predominantly fast fibered ankle extensor muscle such as the plantaris is functionally overloaded by the surgical removal of its synergists, it responds by hypertrophying all of its fibers (4,30). This enlargement enables the muscle to potentially generate more absolute force to meet a wide spectrum of functional demands (25). In addition, a subpopulation of fibers in the deep core of the muscle changes MHC phenotype, whereby fibers thought to express primarily either the IIa or IIx isoforms are induced to express chiefly the slow (Type I) isoform(4,30,36). In another spectrum of plantaris muscle fibers, originally comprised chiefly of the IIb MHC, the change in phenotype in response to the overload is limited to a transformation whereby the IIx and/or IIa MHC is upregulated while that of the IIb MHC is downregulated (11,30). Thus, the adaptive process in response to mechanical loading results in both fiber enlargement and a net transformation in contractile protein phenotype favoring predominant expression of slower MHC isoforms.In rodent cardiac muscle, this type of manipulation can be mimicked experimentally by elevating the blood pressure (afterload) against which the heart must deliver blood (18,29). This condition induces a similar adaptation to that seen in skeletal muscle in that the cardiac cells both enlarge and transform MHC phenotype whereby the slow (beta) MHC is upregulated while the alpha MHC is downregulated(18,29). In this model system, the functional properties (contractility state) are lowered in accordance with the relative change in MHC phenotype.Responses to a decrease in weight bearing activity and weightlessness. Two approaches have been used to reduce the load-bearing activity of skeletal muscle in rodents. The first involves the model of hindlimb suspension in which the lower extremities are prevented from weight bearing. The second approach involves exposing animals to the weightless environment of spaceflight. In both of these conditions a number of common adaptations have been observed. These include 1) atrophy of both slow-twitch and fast-twitch fibers comprising muscles used in weight bearing and locomotion (6,9,10,26), 2) a change in contractile protein isoform expression reflecting a faster phenotype for controlling both cross bridge and calcium cycling processes(6,9,10,12,17,20,26,28), 3) corresponding changes in the functional properties of the muscle manifesting a speeding of shortening and relaxation properties(9,10,12), 4) a reduction in both the absolute and relative force and power generating properties of antigravity soleus (9,10), and 5) a shift in the force frequency patterns of the muscle whereby a greater frequency of electrical stimulation (i.e., action potential frequency) is needed to generate submaximal levels of force output (9,10). These changes are summarized in Table 1. Although there is not a similar model for unloading the heart as described for skeletal muscle, our studies have shown that when the arterial blood pressure is chronically reduced below normal levels in rodents by treatment with agents to reduce circulating levels of angiotensin II, the heart responds by both atrophying and increasing the relative expression of the cardiac fast, alpha MHC isoform(18). Thus, these data suggest that muscle mass is reduced and faster contractile protein phenotypes are favored by striated muscle when the operational load it works against is reduced.TABLE 1. Effects of functional overload and muscle unloading on the gross morphology, fiber size, functional properties, and contractile protein expression of antigravity and locomotor skeletal muscle.Effects of Altered Loading States on Other Biochemical and Metabolic Properties of Skeletal MuscleRecent findings also suggest that other organelles within the muscle fiber may be regulated in accordance with the type of myosin that is expressed. For example, studies show that muscles with fast contractile velocities have fast relaxation properties and also express high levels of glycogenolytic enzymes to produce energy via anaerobic processes (2). Other studies show that during unloading there is upregulation of both the calcium release and sequestering pumps (20,28) and that these changes are associated with increased glycogenolytic enzyme expression in slow skeletal muscle (26). In contrast, when fast muscles are functionally overloaded, there is downregulation of glycogenolytic enzyme levels in the overloaded muscle, which is consistent with the slower myosin phenotypes being expressed (2,4). Surprisingly, however, available information suggests that the sarcoplasmic reticulum system is not comcomitantly downregulated in accordance with the induction of a slower MHC contractile phenotype (25). Thus, certain subcellular components within muscle may not always be tightly coregulated (Table 1).When one examines the effects of loading state on the regulation of oxidative metabolic processes, no clear-cut patterns are observed(Table 2). For example, in slow skeletal muscles such as the soleus, both the states of functional overload and of unweighting appear to reduce the muscle's capacity to oxidize long chain fatty acids under state 3 conditions (3,7). However, the capacity to oxidize the carbohydrate end product, pyruvate, is only compromised under conditions of functional overload (3,7). In a fast muscle such as the plantaris, both functional overload and unweighting have a relatively small effect on the oxidation capacity for pyruvate(3,7); however, the capacity to oxidize long chain fatty acids is clearly compromised following exposure to microgravity(7). Thus, the adaptive process involving the oxidative machinery is both tissue specific and stimulus specific. Clearly, more research is needed to unravel the adaptive processes involving these complex metabolic pathways in response to altered loading states.TABLE 2. Effects of functional overload and weightlessness on the oxidative and glycogenolytic properties of fast and slow skeletal muscle.Functional Significance to the Adaptive Processes Involving Altered Loading StatesThe hallmarks of a functionally overloaded fast skeletal muscle are an increased muscle mass in combination with expression of a slower MHC phenotype. These adaptations enable the muscle to generate more absolute force and power (25). Also, with an expansion in the slow myosin pool, the maintenance of submaximal force should be more economical because more slow twitch fibers (and likely motor units) should be available for recruitment. This is consistent with our previous observations demonstrating that the resistance to fatigue is enhanced when an overloaded muscle is stimulated to perform repetitive isometric contractions(5). On the other hand, following a state of unloading in which muscles used for both antigravity and locomotor function undergo both atrophy and a transformation in some of the fibers to express more fast contractile protein phenotypes, the opposite occurs; i.e., the muscle produces less absolute maximal force and power, and, in the case of a slow muscle, it becomes more fatiguable when performing repetitive isometric contractions(9). Further, there is a potential to require carbohydrate as the primary substrate energy source (7). Consequently, the endurance capacity of the organism could become compromised during sustained exercise if the total body glycogen stores become depleted. Thus, states of unloading could compromise the work capacity of astronauts when their muscles must perform work under some degree of loading, i.e., performing extravehicular activity in cumbersome space suits during spaceflight and/or performing emergency egress during return to a 1 G environment.Mechanisms of Striated Muscle Plasticity in Response to Altered Unloading StatesAdaptations involving a change in the quantity and/or quality of protein expression in response to altered mechanical activity theoretically can be regulated at several stages of control. As shown in Figure 2), these could involve transcriptional, pretranslational, translational, and posttranslational processes. In light of the types of adaptations discussed, all of these processes are likely playing a pivotal role.Figure 2-Schematic diagram depicting the chain of events in the control of protein turnover in mammalian cells. See text for further details.Alterations in muscle mass. The data clearly suggest that the gross amount of mechanical activity impacting striated muscle affects the absolute amount of protein that it maintains. For example, during states of hindlimb unweighting, the rate of total protein synthesis (a translational process) is significantly reduced within the first few hours of creating the unloaded state (21,23). This is coupled with a subsequent transient increase (over the next few days) in the rate of protein degradation (33), thereby resulting in a ≈50% smaller protein pool comprising the muscle, i.e., the muscle becomes significantly atrophied (32). While the signal transducing process(es) associated with atrophy response remains unknown, the involvement of either growth factor inactivation processes or the catabolic actions of other hormones could be involved(1,8,16,23). For example, mRNA signals for insulin like growth factor-1 (IGF-1) expression in skeletal muscle have been reduced in hindlimb muscle when the weight-bearing activity of the animal is reduced (8). In contrast, preliminary results from our laboratory suggest an opposite response when a skeletal muscle is functionally overloaded, i.e., IGF-1 expression is enhanced (G. R. Adams, personal communication). Recent studies on cardiac muscle further suggest that IGF-1 expression is linked to the loading state imposed on the system(15). Whether additional hormonal factors are involved in the atrophy response is uncertain. In this context, there appears to be a critical interplay between mechanical factors and growth stimulation factors in the maintenance of muscle mass when challenged by a state of unloading(16,22,23). Furthermore, the time course of the muscle atrophying response to unweighting is altered when cellular glucocorticoid receptors are pharmacologically blocked(1). Also, under conditions involving muscle wasting in response to glucocorticoid treatment, a key enzyme, glutamine synthase, is upregulated by elevations in the circulating level of this hormone(19). This enzyme is thought to regulate both the formation and the release of the amino acid, glutamine (i.e., the primary amino acid to which most amino acids are converted to during the protein degradation process) from the muscle during the wasting process. Experiments in which the level of glutamine is artificially elevated in both the plasma and muscle during glucocorticoid treatment markedly prevent both the atrophy process and the decrease in total protein and myosin protein synthesis rates that occur under these conditions (19). On the other hand, agents that are thought to inhibit the proteosome axis in the protein degradation process appear to be partially effective in ameliorating the atrophy response to weightlessness (34). Clearly more research is needed to examine the interaction of hormonal and activity factors in the regulation of protein synthetic and degradation processes that affect the degree of atrophy associated with muscle unloading.Alterations in myosin phenotype. Recent findings involving both cardiac and skeletal muscle suggest that transcriptional and pretranslational control of the slow MHC gene is highly regulated by thyroid hormone (T3)(13,30,31). For example, T3, in conjunction with its nuclear receptor and other nuclear regulatory proteins, acts as a negative modulator of transcription of the beta MHC gene while concomitantly exerting positive transcriptional control of the alpha MHC gene(13,30,31). Thus, it is interesting that T3 treatment, in combination with functional overload, inhibits the upregulation of slow myosin expression typically seen under these conditions of mechanical loading (30). In contrast, the downregulation of the slow myosin gene typically seen during states of unloading can be inhibited by making the animals hypothyroid(13). These findings suggest that changes in loading state may alter the muscle's responsiveness or sensitivity to thyroid hormone. Furthermore, recent findings on cardiac muscle suggest that transcription of the beta MHC gene can be positively regulated by expression of a nuclear factor(s) that binds to a specific DNA sequence (designated as beta e2) upstream of the gene's transcriptional initiation site(31). This factor can be upregulated in the rodent heart in response to pressure overload (31). Thus, a complex interaction of mechanical- and hormonal-induced transcriptional factors appear to be involved in regulating MHC plasticity in response to altered states of muscle loading.Role of resistance exercise as a countermeasure to muscle atrophy. Recent findings on both human and animal models of unloading-induced muscle atrophy suggest that bouts of resistance exercise involving high force output of either the concentric or isometric type can be effective in partially blunting the atrophy process(14). These types of activity affect pretranslational, translational, and posttranslational processes(11,23,24,37). In rodents as little as 40-50 four-s high resistance contractions per workout every other day were effective in partially blunting the atrophy response seen during hindlimb suspension (14). The potential impact of resistance training as a countermeasure to unloading-induced atrophy can be put into greater perspective by the fact that it takes only 8 min·wk-2 of resistance exercise compared to either 640 min·wk-1 of endurance running or 840 min·wk-1 of stationary standing to achieve about a 40% reduction in the degree of atrophy that occurs in rodent antigravity skeletal muscle in response to hindlimb suspension(14,32). These observations suggest that resistance exercise should be considered essential for astronauts to maintain both body and muscle homeostasis during spaceflight. Furthermore, because of the strong interaction of load-bearing stress and growth/hormonal factors in the management of muscle mass in the face of states of unloading(4,16,22,23), further insight is needed in this integrated area of study.Future Research DirectionsThe findings reported herein indicate that future research needs to focus in greater depth on the mechanisms and processes whereby muscle protein turnover is regulated (Fig. 2). This research should involve studies that target both the processes of protein synthesis and protein degradation because the balance of these two processes determines the steady state level of muscle mass. 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