The adaptive response of skeletal muscle: What is the evidence?

Adult skeletal muscle is capable of adapting its properties in response to changing functional demands. This now sounds like a statement of the obvious, and many people assume it has always been this way. A mere 40 years ago, however, the picture was entirely different. In this Review and personal memoir, I outline the scientific context in which the theory was generated, the objections to it from entrenched opinion, and the way those objections were progressively met. The material should be of some historical interest, but, more importantly, it collects together the full range of evidence on which the current paradigm is based. Muscle Nerve 57: 531-541, 2018.

Practical and effective stomal sphincter creation: evaluation in pigs.

PURPOSE: Stoma creation frequently presents complications for which there is no satisfactory surgical solution. We reexamined the feasibility of managing stoma continence with an artificial sphincter, addressing the outstanding issues of geometry, electrode disposition, and fatigue resistance. METHODS: In 6 pigs, 1 rectus abdominis muscle was preconditioned with electric stimulation for 4 weeks by an implanted stimulator. A sphincter was then constructed and tested for its ability to provide continence against saline at a typical intestinal pressure. The result was compared with a sphincter fashioned from the unconditioned contralateral (control) muscle. In each case, stimulation was applied alternately to longitudinal segments. RESULTS: A 2-layered wrap was required to achieve continence. Sphincters created from the preconditioned muscles could sustain continence continuously for at least 90 minutes. CONCLUSION: This study establishes a practical approach to the creation of a sphincter from the rectus abdominis muscle in stoma patients. Continence can be achieved only with a double-layered wrap. Fatigue during long-term operation can be avoided by a combination of preconditioning and segmental stimulation of intramuscular nerve branches.

Adaptive change in electrically stimulated muscle: a framework for the design of clinical protocols.

Adult mammalian skeletal muscles have a remarkable capacity for adapting to increased use. Although this behavior is familiar from the changes brought about by endurance exercise, it is seen to a much greater extent in the response to long-term neuromuscular stimulation. The associated phenomena include a markedly increased resistance to fatigue, and this is the key to several clinical applications. However, a more rational basis is needed for designing regimes of stimulation that are conducive to an optimal outcome. In this review I examine relevant factors, such as the amount, frequency, and duty cycle of stimulation, the influence of force generation, and the animal model. From these considerations a framework emerges for the design of protocols that yield an overall functional profile appropriate to the application. Three contrasting examples illustrate the issues that need to be addressed clinically.

Cardiac assistance from skeletal muscle: a reappraisal.

Cardiac assistance from skeletal muscle offers an attractive surgical solution to the problem of end-stage heart failure, yet it is widely regarded as a failed approach. I argue here that this is an outdated assessment. Systematic progress has been made over the last 25 years in understanding the relevant basic science. In the light of these advances we should be reconsidering the place of skeletal muscle assist in the surgical armamentarium.

Functional electrical stimulation of denervated muscles: an experimental evaluation.

For many years there has been a dearth of effective treatment options for the severe wasting and secondary consequences of motor nerve injury. In recent years, however, an intensive regime of electrical stimulation has been shown to have considerable therapeutic benefits. This article reviews the results of an extensive study designed to address the clinically relevant issues in an appropriate animal model. The study reveals both the benefits and the limitations of the technique, but strongly endorses the therapeutic advantages of introducing a program of stimulation during the initial, nondegenerative phase of the muscle response to nerve or root injury.

Real-time polymerase chain reaction to follow the response of muscle to training.

The adaptive response of muscle to changes in activity or loading can take many weeks. Changes in the levels of RNA within a muscle fiber can give an early indication of the nature of the response of that fiber to changes in activity or loading. We have designed a new primer set for quantitative polymerase chain reaction (PCR) that will allow us to follow these early transcriptional changes in rat muscle, and have shown that analysis can be performed by standard techniques on as little as 5 mg of muscle, an amount that can be obtained by needle biopsy.

Therapeutic stimulation of denervated muscles: the influence of pattern.

Muscular atrophy due to denervation can be substantially reversed by direct electrical stimulation. Some muscle properties are, however, resistant to change. Using a rabbit model of established denervation atrophy, we investigated whether the extent of restoration would vary with the stimulation protocol. Five patterns, delivering 24,000-480,000 impulses/day, were applied for 6 or 10 weeks. The wet weight, cross-sectional area, tetanic tension, shortening velocity, and power of denervated muscles subjected to stimulation all increased significantly. The fibers were larger and more closely packed and there was no evidence of necrosis. There was a small increase in excitability. Isometric twitch kinetics remained slow and fatigue resistance did not improve. The actual pattern of stimulation had no influence on any of these findings. The results, interpreted in the context of ultrastructural changes and an ongoing clinical study, reaffirm the clinical value of introducing stimulation during the initial non-degenerative phase. They indicate that there would be little therapeutic benefit in adopting regimes more energetically demanding than those in current use, and that the focus should now shift to protocols that represent the least intrusion into activities of daily living.

Effects of chronic electrical stimulation on long-term denervated muscles of the rabbit hind limb.

We investigated the extent to which activity induced by chronic electrical stimulation could restore the mass and contractile function of rabbit tibialis anterior (TA) muscles that had undergone atrophy as a result of prolonged denervation. Denervation was carried out by selectively interrupting the motor nerve branches to the ankle dorsiflexors in one hind limb. Stimulators were implanted, with electrodes on the superficial and deep surfaces of the denervated TA muscle. Ten weeks later, the mass and mid-belly cross-sectional area (CSA) of TA muscles subjected to denervation alone had fallen to approximately 40% of normal. At this stage, stimulators in the other rabbits were activated for 1 h/day to deliver 20-ms rectangular bipolar constant-current pulses of 4 mA amplitude at 20 Hz with a duty cycle of 1s ON/2s OFF, a total of 24,000 impulses/day. The animals were examined after a further 2, 6 or 10 weeks. Stimulation restored the wet weight of the denervated muscles to values not significantly different to those of normal, innervated controls. It increased CSA from 39% to 66% of normal, and there was a commensurate increase in maximum isometric tetanic force from 27% to 50% of normal. Light and electron microscopic examination revealed a marked improvement in the size, packing, and internal organization of the stimulated-denervated muscle fibres, suggestive of an ongoing process of restoration. Excitability, contractile speed, power, and fatigue resistance had not, however, been restored to normal levels after 10 weeks of stimulation. Similar results were found for muscles that had been denervated for 39 weeks and then stimulated for 12 weeks. The study demonstrates worthwhile benefits of long-term electrical stimulation in the treatment of established denervation atrophy.

A control system for automatic electrical stimulation of abdominal muscles to assist respiratory function in tetraplegia.

This letter refers to a paper published by Gollee et al. [Gollee H, Hunt KJ, Allan DB, Fraser MH, McLean AN. A control system for automatic electrical stimulation of abdominal muscles to assist respiratory function in tetraplegia. Med Eng Phys 2007;29:799-807]. We address here the consequences of continuous use and suggest a refinement that may improve the cough peak flow under more chronic conditions.

Adaptive conditioning of skeletal muscle in a large animal model (Sus domesticus).

Recognition of the adaptive capacity of mammalian skeletal muscle has opened the way to a number of clinical applications. For most of these, the fast, fatigue-susceptible fibres need to be transformed stably to fast, fatigue-resistant fibres that express the 2A myosin heavy chain isoform. The thresholds for activity-induced change are size-dependent, so although the requisite patterns of electrical stimulation are known for the rabbit, in humans these same patterns would produce type 1 fibre characteristics, with an undesirable loss of contractile speed and power. We have used histochemistry, immunohistochemistry and electrophoretic separations to evaluate a possible conditioning regime in a large animal model. Stimulation of the porcine latissimus dorsi muscle with a phasic 30-Hz pattern for up to 41 days converted all type 2X and 2A/2X fibres to 2A with only a small increase in the type 1 population, from 17% to 22%. Stimulation for longer periods increased the proportion of type 1 fibres to 52%. Based on this model, stimulation regimes designed to achieve a stable 2A phenotype in humans should deliver fewer stimulating impulses, possibly by a factor of 2, than the pattern assessed here. Any such pattern needs to be tested for at least 8 weeks.

Counterpulsation from the skeletal muscle ventricle and the intraaortic balloon pump in the normal and failing circulations.

BACKGROUND: The intra-aortic balloon pump (IABP) is the device that is in most common use to provide cardiovascular support. A skeletal muscle ventricle (SMV) was configured to produce counterpulsation in the thoracic aorta similar to that obtained with an IABP. The hemodynamic effects of an IABP and a SMV in the same animal and in both normal and failing circulations were assessed. METHODS AND RESULTS: SMVs were connected to and IABPs were placed in the thoracic aorta of 12 anesthetized pigs. Hemodynamic parameters during the IABP- or the SMV-assisted beat were compared with those during the preassist beat. Acute heart failure was induced in 6 of the pigs by snaring the left anterior descending coronary artery (LAD). The hemodynamic effects of the IABP and the SMV were then reassessed. In the assisted cycles, SMV activation increased the mean aortic diastolic pressure (MADP) by 26.5+/-3.5%, the mean diastolic LAD flow by 48.4+/-7.2%, and endocardial viability ratio (EVR) by 31.6+/-3.8% (P<0.0001). In the same animals, IABP assist increased MADP by 19.8+/-2.3%, mean diastolic LAD flow by 37.2+/-3.9%, and EVR by 21.4+/-3.0% (P<0.0001). Under acute heart failure conditions, both SMV and IABP assist significantly increased MADP, mean diastolic LAD flow, and EVR. CONCLUSIONS: In both the normal and failing circulations, the SMV was an effective counterpulsator, providing cardiac assist that was at least equal to that available from an IABP. The SMV may therefore provide the proven benefits of an IABP in ambulant patients.

Functional electrical stimulation of denervated muscles: basic issues.

Denervating injuries result in flaccid paralysis and severe atrophy of the affected muscles. This work reviews the potential for functional restoration of such muscles by electrical stimulation, focusing on the basic scientific issues.

Determination of the chronaxie and rheobase of denervated limb muscles in conscious rabbits.

Measurements of the rheobase and chronaxie can be used to define the excitability of nerves and muscles. The aim of this study was to obtain a record over many weeks of changes in the rheobase and chronaxie of denervated rabbit tibialis anterior muscle (TA). A custom-built electronic stimulator was implanted into the peritoneal cavity of New Zealand White rabbits. Large stainless steel electrodes were placed on the denervated TA muscle. Rheobase and chronaxie were measured noninvasively at weekly intervals by means of a laptop PC, which communicated with the stimulator via a radio-frequency link. At each setting the denervated TA was palpated manually to detect the response of the muscle. During the first few days after denervation the rheobase increased transiently to 0.8 +/- 0.13 mA, approximately twice the value for normal innervated muscle, then decreased to normal for the remainder of the experimental period. Chronaxie underwent a significant 3-fold increase from 4.5 +/- 1.1 ms to 14.1 +/- 1.1 ms during the first two weeks of denervation and remained elevated throughout. The custom-built implantable electronic stimulator allowed changes in muscle excitability to be studied over a long period of denervation within individual animals, providing an accurate assessment of the time course of denervation-induced changes in muscle excitability.

Recovery of long-term denervated human muscles induced by electrical stimulation.

We investigated the restorative potential of intensive electrical stimulation in a patient with long-standing quadriceps denervation. Stimulation started 18 months after injury. After 26 months, the thighs were visibly less wasted. Muscle cross-sectional areas, measured by computerized tomography, increased from 36.0 cm(2) to 57.9 cm(2) (right) and from 36.1 cm(2) to 52.4 cm(2) (left). Knee torque had become sufficient to maintain standing without upper extremity support. Biopsies revealed evidence of both growth and regeneration of myofibers. The results suggest that electrical stimulation may offer a route to the future development of mobility aids in patients with lower motor neuron lesions.

A nonradioactive assay for nitric oxide synthase activity in tissue extracts.

We describe a fluorescence assay for nitric oxide synthase activity based on a new indicator, 4,5-diaminofluorescein (DAF-2). The method offers the advantage of being safer and more convenient than the citrulline radioassay in common use. The rapid and irreversible binding of DAF-2 to oxidized nitric oxide (NO) enables NO production to be measured in real time. The protocol is applied to the measurement of nitric oxide synthase in crude extracts of skeletal muscle.

Skeletal muscle ventricles with a single-limb conduit: the importance of hemodynamic design.

BACKGROUND: Skeletal muscle ventricles (SMVs) connected to the descending thoracic aorta have the potential for providing long-term diastolic augmentation. A successful existing design employs a bifurcated conduit, but aortic constriction between the limbs of the conduit is required to ensure obligatory flow-through. Here we evaluate an alternative approach in which connection to the aorta is made by a single-limb conduit. METHODS: In two groups of dogs SMVs were constructed from the left latissimus dorsi muscle and connected to the circulation via a single-limb conduit of length 110-120 mm (Group 1, n = 5) or 70 mm (Group 2, n = 5). The animals were followed over 10 weeks. RESULTS: Although all animals showed significant augmentation of diastolic aortic pressure at the outset, substantial thrombus developed in the SMVs of both groups. The results were analyzed by reference to design criteria for a single-limb conduit SMV, developed from empirical, in-vitro flow studies and formulated mathematically. CONCLUSION: The SMVs constructed in this experiment appeared to meet the criteria for adequate mixing of blood within the ventricle. They did not, however, achieve adequate exchange of blood with the circulation. Thrombosis was therefore attributable to excessive residence time of blood in the SMV and conduit. Both the experimental study and the mathematical analysis point to the need for SMVs of this configuration to be constructed closer to the aorta. Preliminary results are reported for such an experiment in the pig, in which the SMV was thrombus-free when terminated electively after 1 week.