Collectively, the tradeoffs for space were referred to by Rome and Linstedt (39) as the “zero sum game.” Some might extend this concept to basically state that muscles and muscle fi bers are perfectly adapted to the physiologic tasks that they perform. In this context, Weibel, Taylor, and Hoppeler (40) proposed the concept of “optimality” of design in physiologic structures—the concept of symmor- phosis. This was defi ned as the perfect matching of struc- ture to functional need, such that no excess capacity was maintained. In terms of energetic effi ciency, the metabolic cost of building and maintaining structures superfl uous to maximal performance should be prohibitive. Given the perspective described relative to the three-compartment model, the concept of symmorphosis would postulate, for instance, that mitochondrial volume density is perfectly matched to the energetic requirements of the SR and myo- fi brils. Certainly, the adjustment of muscle structure to higher functional demands ( i.e. , training), and the reverse when training ceases, suggests a cost-to-benefi t relation- ship may help shape “optimization” of muscle.
The notion of economical design in animals is not a recent one, but the formulation of symmorphosis has been a stimulus to much interesting research. It is an appealing and seemingly intuitive concept of design and the discussion of the applicability of economy of struc- tural costs to the evolution of organisms is a very fruitful area of investigation. However, as Diamond and Ham- mond (41) remarked, “The concept is worth posing not because we believe it to be literally true, but because only by posing [it]. . . can one hope to detect where it breaks down, and to identify the interesting reason for its breakdown.”
As stated previously, the briefest mechanical event that a muscle can produce is an isometric twitch and this is sim- ply the response to a single stimulus. The amplitude and time course of a twitch are defi ned by factors 1 to 4 shown in Figure 4.5. The duration of a twitch can be quite short in some vertebrates, whereas in others it can be much longer.
For instance, in sonic muscles of some fi sh (used for mat- ing), the total twitch duration is very short (10–20 ms) and the muscles can operate at frequencies of 100 to 200 Hz. Similarly, the shaker muscles of rattlesnakes also have short twitch durations and can operate at frequencies of 90 Hz. Human skeletal muscle fi bers, in contrast, have isometric twitch durations that are much longer ( e.g. , 250 ms), and as a consequence are confi ned to operate at low frequencies ( e.g. , 2–5 Hz).
As eloquently addressed by Rome and Linstedt (39), the simple contrast between sonic and shaker muscles brings forth some important design considerations that can be summarized as follows: Ultimately, the performance of a muscle is largely dependent on the distribution of SR, myo- fi brillar, and mitochondrial volumes. These general design considerations can be illustrated using the following exam- ples. Muscles that operate at high frequencies are obligated to have fast Ca cycling kinetics and, as a result, a rela- tively large proportion of cell volume must be dedicated to the SR (in some instances 25% of the cell volume). If such muscles are active for long periods of time, then a signifi - cant amount of the cell volume must also be dedicated to the mitochondria. In such muscles, the myofi brillar volume will be relatively small and the muscles will be incapable of generating large forces when normalized to cross- sectional area. Alternatively, if the muscles are active for only short durations, then a much greater proportion of the cell vol- ume can be occupied by myofi brils, allowing the muscle to generate moderate to large forces. The myofi brillar volume density will be greatest in muscles optimized to produce force but, in these muscles, the tradeoff is that they will not be able to operate at high oscillatory frequencies or sup- port high levels of metabolic activity. Finally, muscles that are required to support high metabolic levels for prolonged periods of time (like fl ight muscles) must have large mito- chondrial volumes ( e.g. , 35% of the total cell volume), and this will correspondingly impose limitations on the SR and myofi brillar volumes and the functions they support.
KEY POINT
Most human skeletal muscles appear to be optimized for myofi brillar volume, suggesting that the generation of force may have been a prime factor in the evolution of human muscles.
TEST YOURSELF
From a comparative perspective, describe how gait frequency, fi ber type, and sarcoplasmic reticulum scale with body mass within mammals. Relate your fi nd- ings to so-called work loops and the ability to realize mechanical work and power.
Herein lies one of the unique aspects of contractile protein isoforms given the three-compartment model ( i.e. , SR, myofi bril, mitochondria). The presence of contractile
ACKNOWLEDGMENTS
The authors would like to acknowledge the insight and comments of Dr. Kenneth M. Baldwin. This work was sup- ported in part by National Institutes of Health grants AR 46856 (VJC) and NIH F32 AR47749 (BCR).
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150 SECTION 1 Exercise and Responses of Biologic Systems
A MILESTONE OF DISCOVERY
It is widely recognized that the structural and functional properties of skeletal muscles are under the infl uence of neural, mechanical, and hormonal factors. Although the specifi c rules of muscle plasticity remain to be completely elucidated, there have been signifi cant strides made on a number of fronts. Much of what has evolved emanated from landmark studies like that of Buller, Eccles, and Eccles. In this classic study, these investigators utilized a
“cross-innervation” or “cross-union” paradigm whereby the slow soleus muscle of cat was reinnervated with the motor nerve innervating the fast fl exor digitorum lon- gus (FDL) muscle, and the FDL was reinnervated with the motor nerve from the soleus muscle. On the contralateral side, the motor nerves innervating a given muscle were simply cut and the ends were resutured together. By con- trasting the cross-innervated group with the reinnervated group, Buller, Eccles, and Eccles were able to account for changes induced by cross-innervation (Fig. 4.10).
Remarkably, these investigators observed that the cross-innervated slow soleus muscle adopted the functional properties of a fast muscle while the cross-innervated fast FDL developed slower contractile properties. This occurred without any corresponding changes in the properties of the motor neurons. On the surface, these fi ndings appear to agree with the “frequency” hypothesis, which simply states that the low fi ring frequency of motor neurons innervat- ing the soleus muscle would cause the FDL to transition to a slower muscle, and the converse would be true of the high fi ring frequency of the motor neurons innervating the FDL. Interestingly, Buller, Eccles, and Eccles did not inter- pret these fi ndings to support the frequency hypothesis.
Rather, they reasoned that if the frequency hypothesis were correct, then the complete cessation of stimulation
should produce an even slower phenotype, which it did not. Their reasoning was apparently based on directional changes in fi ring frequency (i.e., progressively lower fi ring frequencies produce progressively slower phenotypes and vice versa).
Buller, Eccles, and Eccles also tested the “aggregate”
hypothesis, which stipulated that the slow tonic fi ring pat- tern of the soleus motor nerve would result in a greater aggregate of impulses and, as a result, a slower phenotype, whereas the phasic fi ring pattern of the a fast motor nerve would produce a smaller aggregate and thereby faster contractile properties. The cross-innervation fi ndings were certainly consistent with this hypothesis. However, Buller, Eccles, and Eccles observed that a complete lack of activa- tion (as studied by spinal isolation) actually caused a fast muscle to become slower and not faster as predicted by the aggregate hypothesis. Having rejected both the fre- quency and aggregate hypotheses, these investigators pro- posed the “chemical” hypothesis, which stated that motor neurons control the contractile properties of skeletal mus- cle by releasing a “chemical” (latter referred to as trophic) substance that traverses the neuromuscular junction and then spreads along the length of the muscle fi ber. Some 45 years later, it is still unclear whether a trophic substance is produced by motor neurons; however, it is clear that this landmark study shaped several generations of scientifi c investigation and provided critical evidence to demonstrate that skeletal muscle possessed a plasticity that was previ- ously unrecognized.
Buller AJ, Eccles JC, Eccles RM. Interaction between motoneu- rones and muscles in respect of the characteristic speeds of their responses. J Physiol. 1960;150:417–39.
Tonic
Slow Fast
Phasic Tonic Phasic
FDL Soleus
Control Cross-Innervation
Slow Fast
FDL Soleus
FIGURE 4.10 The cross-innervation experiment of Buller, Eccles, and Eccles in which the motor nerve to the fl exor digitorum longus muscle (FDL) was changed to innervate the soleus muscle, whereas the motor nerve to the soleus muscle was altered so it would innervate the FDL muscle.
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CHAPTER 4 The Muscular System: Structural and Functional Plasticity 151
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33. Edman KA, Reggiani C, Schiaffi no S, et al. Maximum velocity of shortening related to myosin isoform composition in frog skeletal muscle fi bres. J Physiol. 1988;395:679–694.
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152
The Muscular System:
The Control of Muscle Mass
Richard Tsika
CHAPTER 5
Abbreviations
Akt Cytosolic protein kinase recruited to the membrane when PI(3)K is activated (also known as PKB)
ATPase Adenosine triphosphatase
Atrogin-1 E3 ubiquitin ligase also called muscle atrophy F-box (Atrogin-1)
bp Base pair
CaMK Calcium-calmodulin protein kinase CaN Calcineurin
Cb1-b Casitas b-lineage lymphoma-b; an E3 ubiquitin ligase
CsA Cyclosporin A
FoxO Forkhead box O; a transcription factor GDF-8 Growth differentiation factor-8; also
termed myostatin
GSK-3 Glycogen synthase kinase-3
HDAC Histone deacetylase
HS Hind limb suspension IGF-1 Insulin-like growth factor-1 MAPK Mitogen-activated protein kinase MCK Muscle creatine kinase
MEF2 Myocyte enhancer factor-2
MOV Mechanical overload
mTOR Mammalian target of rapamycin
MuRF1 Muscle ring fi nger 1 MuRF3 Muscle ring fi nger 3 MyHC Myosin heavy chain
NFAT Nuclear factor of activated T-cell nNOS Neuronal nitric oxide synthase p70 S6K Kinase that phosphorylates the S6 sub-
unit of ribosomes
PHAS-1 Phosphorylated heat- and acid-stable protein-1; also known as 4E-BP1
PI(3)K Phosphatidylinositol-3-OH kinase Pur /Pur Purine-rich; and isoforms, single-
stranded DNA and RNA binding proteins PKD1 Polycystic kidney disease 1; cytosolic pro-
tein kinase involved in calcium regulation of cell signaling
Ras Monomeric GTP-binding protein
Sm Slow myosin
Sp1 Specifi c protein 1 Sp3 Specifi c protein 3
TEAD-1 Transcriptional enhancer factor-1 V max Maximum unloaded shortening velocity Work Force distance
YB-1 Y-box binding protein; single-stranded DNA and RNA binding protein
Introduction
An extraordinary characteristic of adult skeletal mus- cle is its intrinsic ability to adapt to a broad range of physiologic stimuli, such as those produced by vari- ous exercise paradigms. For example, increased skel- etal muscle workload (force distance) as imposed by various weight training regimens has a profound effect on both mass (hypertrophy) and strength (force
production) (1,2). This type of adaptation in response to weight training is so well known it is legendary. Milo of Crotona, a sixth century BC Greek athlete, reportedly acquired the strength to carry a bull around a stadium by lifting the bull daily from the time it was a newborn calf, thereby gradually accommodating to the increased load as the calf increased in weight (3). Conversely, decreased muscle loading associated with inactivity resulting from normal aging processes, immobilization
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CHAPTER 5 The Muscular System: The Control of Muscle Mass 153