Increased depolarization, prolonged recovery and reduced adaptation of the resting membrane...

Mechanisms of Ageing and Development

155 (2000) 127–138

Increased depolarization, prolonged recoveryand reduced adaptation of the resting

membrane potential in aged rat skeletal musclesfollowing eccentric contractions

Todd McBride *Department of Biology, California State Uni6ersity, Bakersfield, CA 93311, USA

Received 6 January 2000; received in revised form 27 March 2000; accepted 27 March 2000

Abstract

Previously it was shown in young-adult muscles that eccentric contractions (EC) producea significant (24 h) depolarization of the resting membrane potential (RMP), and thatin-vitro (Gd3+) and in-vivo (streptomycin) blockade of stretch activated ion channels (SAC)result in a partial repolarization of the RMP. The portion of the depolarization not restoredby SAC blockade is believed to be from sarcolemmal injury. A second exposure to EC resultsin less depolarization and a more rapid recovery of the RMP. Aged muscles were subjectedto the same EC protocol to test the hypotheses that: (1) Aged muscles will experience a moresignificant and prolonged depolarization of the RMP following EC. (2) The depolarizationin aged muscles will occur by a greater contribution from membrane damage, rather than theopening of SAC. (3) The aged muscles will demonstrate a reduced capacity to adapt to EC,and will experience a similar degree of depolarization following repeated exposures to EC.The results indicate a significantly greater and longer lasting depolarization in aged com-pared to young-adult muscles. Blocking SAC did not produce a repolarization of the RMPin aged muscles. Aged muscles had a significantly reduced adaptive response to ECcompared to young-adult. It is speculated that the different response in aged muscles resultsfrom a reduced number of functional SAC. © 2000 Elsevier Science Ireland Ltd. All rightsreserved.

Keywords: Stretch-activated channels; Aged; Muscle; Eccentric contractions

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* Tel.: +1-661-6643025; fax: +1-661-6656956.E-mail address: [email protected] (T. McBride)

0047-6374/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved.

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T. McBride / Mechanisms of Ageing and De6elopment 115 (2000) 127–138128

1. Introduction

Functional and morphological changes in skeletal muscle with aging have beenwell documented, and several excellent reviews are available (Ermini, 1976; Grimbyand Saltin, 1983; McCarter, 1990; Rogers and Evans, 1993; Brooks and Faulkner,1994). In general there is a loss of muscle mass and strength with aging. Someattribute the loss in mass to a reduction in muscle fiber numbers (Lexall et al.,1988), particularly type II (Larson and Edstrom, 1986). While others attribute theloss in mass to an atrophy of existing fibers (Brown, 1987). Either way it is agreedthat there is a decline in the overall muscle mass with aging. The decline in mass isaccompanied by a reduction in peak muscle tension, particularly during tetaniccontractions (Brooks and Faulkner, 1988; McBride et al., 1995). This is due in partto the reduction in mass, but additional changes occur as the specific tension alsodeclines (Brooks and Faulkner, 1988; McBride et al., 1995). Despite a loss in musclemass and strength, aged muscle responds positively to a high resistance trainingprogram by increasing muscle strength (Frontera et al., 1988; Klitagaard et al.,1989; Brown et al., 1990) and muscle fiber cross sectional area (Brown, 1989; Brownet al., 1992).

Repeated exposures to eccentric contractions (EC) provide an effective signal formuscle cell hypertrophy and strength gains (Hather et al., 1991; Higbie et al., 1996).However, hypertrophy and strength gains are preceded in the early stages of aneccentric training program by damage to muscle cells accompanied by reducedcontractile function (Armstrong, 1990). The damage is temporary, and as themuscles recover contractile function they become resistant to damage followingsubsequent exposures (Clarkson and Tremblay, 1988a; Sacco and Jones, 1992;McBride et al., 1995). Aged muscles are more susceptible to eccentric inducedmuscle damage (Brooks and Faulkner, 1996) and take longer to recover (Brooksand Faulkner, 1990; McBride et al., 1995). Reports of the ability of aged musclesto adapt to eccentric contractions yield varying results. Clarkson and Dedrickfound that aged muscles in human subjects adapt similarly to young, while McBrideet al. report a reduced adaptation in aged rodent muscles following EC (Clarksonand Dedrick, 1988b; McBride et al., 1995).

In addition to the loss in muscle contractile function immediately following EC,there is a significant and sustained depolarization of the resting membrane potential(RMP) of the muscle cells that persists for at least 24 h (McBride et al., 2000).Depolarization occurs due to an increase in Na+ conductance across the sar-colemma. The increase in conductance is the result of the opening of stretchactivated ion channels (SAC) in the sarcolemma, along with physical damage to thesarcolemma (McBride et al., 2000). Blocking SAC with the non-specific SACchannel blocker streptomycin in-vivo prior to EC significantly reduces the depolar-ization. SAC blockade by Gd3+ in-vitro following EC will also result in asignificant repolarization of the RMP (McBride et al., 2000). The role of SAC inmuscle function is unclear, but their activation appears to play an important role inthe remodeling of both cardiac and smooth muscle in response to mechanical strain(Kent et al., 1989; Sadoshima and Izumo, 1993), and they may play a similar role

T. McBride / Mechanisms of Ageing and De6elopment 115 (2000) 127–138 129

in skeletal muscles exposed to EC. This is evident by the reduced ability of musclesto adapt to EC when the SAC are blocked during an initial exposure (McBride etal., 2000).

The purpose of this study was to compare the amplitude and time course ofsarcolemmal depolarization following EC in aged muscles compared to previousmeasurements in young-adult muscles following EC. Tibialis anterior muscles fromaged 32 month rats were exposed to EC to test the hypothesis that aged muscleswould exhibit a greater and more prolonged depolarization of the RMP followingEC, which is followed by a reduced capacity of the sarcolemma to adapt to themechanical strain of EC.

2. Methods

2.1. Animals

Female, Sprague–Dawley rats, 3 months of age were used for the experimentsinvolving young-adult muscles. Female, Fisher 344/BN F1 hybrids, 32 months ofage were used for the experiments involving aged muscles. Animal care and useprotocols followed approved California State University, Bakersfield and NIHguidelines. Animals were housed in a temperature controlled room (19–21°C) witha 12 h light–dark cycle, and were provided unlimited access to standard rat chowand water. Rats were anesthetized with ketamine/rompum (50 mg/kg, i.p.) duringthe exercise protocol and during the terminal experiment. Exercised rats that wereto be evaluated at later time points were placed on a warming pad and allowed torecover from the anesthesia. Those animals not immediately evaluated were re-turned to the animal quarters until the terminal experiment.

2.2. Eccentric exercise protocol

Animals anesthetized with ketamine/rompum (50 mg/kg i.p.) performed low-fre-quency, high resistance exercise on a pulley device similar to that described andillustrated by Wong and Booth (1988). The rat was placed in a prone position onthe supporting platform of the pulley apparatus so that the hind legs extendedbelow the platform. One hind foot was attached directly to the lever arm of thepulley system so that simultaneous contraction of the triceps surae and anteriorankle flexors produced ankle extension and lifted a weight attached to the leverarm. Two monopolar stainless steel needle electrodes were inserted percutaneouslynear the sciatic notch to stimulate the sciatic nerve. Supramaximal stimulation ofthe sciatic nerve caused the posterior ankle extensor muscles (triceps surae) tocontract concentrically, while the ankle flexor muscles contracted eccentrically, inopposition to the stronger ankle extensors. Stimulation consisted of 100 Hzstimulus trains with a train duration of 2.5 s. The exercise paradigm consisted offour sets of six repetitions with a 20 s rest between repetitions and a 5 min restbetween sets. Animals exposed to a second bout of EC were allowed to recover 14


days from the initial exposure. Animals that received a total of four exposures toEC were allowed to recover 7 days between each exposure.

2.3. Electrophysiology

Resting membrane potentials (RMPs) were obtained from control and exercisedtibialis anterior (TA) muscles both in situ and in vitro. Recordings were obtainedusing standard glass microelectrode techniques (McBride et al., 2000). Electrodeswere filled with 3 M KCl and had tip resistances of approximately 20–30 MV. AGrass platinum reference electrode was placed in the proximal end of the TA.RMPs were recorded from TA in situ in anesthetized rats. Animals were placed ona thermal pad to maintain body temperature (37–39°C). The rat and pad werearranged on a metal frame. The hind limb was stabilized by clamping the leg at theknee and ankle, using metal clamps attached to the frame. Control and exercisedTA muscles were exposed and cleared of the outer layers of connective tissue. Themuscles were incubated with 50 ml of type IV collagenase 12 mg/ml (Sigma) for 20min prior to making recordings. Intracellular recordings were obtained fromexercised TA and the contralateral control TA at various time points following ECas indicated in the results. Each exercise group contained at least four animals(unless otherwise indicated), and at least 25 fibers were sampled in each muscle.

RMPs from control and exercised TA were measured in vitro after removing themuscles from anesthetized animals at selected times following the exercise. Theisolated TA was pinned at rest length to the silastic covered bottom of a Lucitechamber filled with 75 ml of HEPES buffered physiological saline (NaCl 150 mM,KCl 5 mM, CaCl2 4 mM, MgCl2 1 mM, glucose 11 mM and HEPES 1.24 mM).The saline solution was maintained at room temperature (21°C) and bubbledcontinuously with 100% O2. Fresh solutions were added to the Lucite chamber afterdraining the chamber through a vacuum line inserted at the base of the chamber.In vitro recordings were obtained from muscle cells to a depth of no more than fivecells from the surface to avoid recording from the hypoxic core of the muscle. Theproximal end of the TA was avoided to prevent recording from fibers damagedduring surgical removal. In-vitro blockade of SAC was performed with Gd3+ at aconcentration of 10 mM (Bustamante et al., 1991). Minimums of 20 measurementsof RMP were obtained from a muscle in the presence of Gd3+.

2.4. Streptomycin treatment

In-vivo blockade of SAC was performed by treating the animals with strepto-mycin 4 g/l in their drinking water (McBride et al., 2000). Treatment began 6 daysprior to the initial exposure to EC. Those animals only receiving a single exposureto EC remained on streptomycin until RMP recordings were performed. Foranimals receiving multiple exposures to EC streptomycin treatment was discontin-ued after the next to last exposure to EC. This resulted in SAC blockade during theinitial exposures, but no SAC blockade during the last exposure prior to RMPrecording.


2.5. Statistics

Results are expressed as the mean9SD of the indicated measurement. Eachtreatment group was compared to its contralateral control, or between age groupswith similar treatments by an unpaired two tail t-test. Differences were accepted asstatistically significant if PB0.05. Analyses were performed using the Statviewsoftware program (Abacus Concepts, Berkeley, CA).

3. Results

3.1. Resting membrane potential following a single no6el exposure to EC

The RMPs measured in muscle cells from young-adult rats were significantlydepolarized (−71.491.5 mV) compared to control (−83.791.8 mV) immediately(1 h) following EC. Muscle cells remained significantly depolarized (−72.492.0mV) 1 day following the novel exposure to EC. The RMPs in young-adult musclesrecovered to normal values (83.691.5) and were not different from controls by 2days post EC (McBride et al., 2000) (Fig. 1). Cells from aged muscles following thesame exercise protocol were also significantly depolarized immediately following EC(−67.891.4 mV) compared to control (−83.590.8 mV) and compared to theyoung-adult exercised muscles. The RMPs remained significantly depolarized

Fig. 1. Means9SD of RMP recorded from control and exercised TA (in vivo) after a single exposureto eccentric contractions. Each mean value represents at least four muscles with recordings from at least25 fibers/muscle, unless otherwise indicated. Control values are represented by the initial starting point.Measurements made at day 0 were recorded within 1–2 h after exercise. Dashed lines and diamonds areaged muscles, solid lines and squares are young adult muscles. * Significantly different (PB0.05) frommean RMP of contralateral control. † Significantly different (PB0.05) from mean RMP of young adult.Day 1, 32 month, N=2.


Fig. 2. Means9SD of RMP recorded from control and exercised TA (in vivo) after a second exposureto eccentric contractions 14 days after the initial exposure. Each mean value represents at least fourmuscles with recordings from at least 25 fibers/muscle, unless otherwise indicated. Control values arerepresented by the initial starting point. Measurements made at day 0 were recorded within 1–2 h afterexercise. Dashed lines and diamonds are aged muscles, solid lines and squares are young adult muscles.* Significantly different (PB0.05) from mean RMP of contralateral control. † Significantly different(PB0.05) from mean RMP of young adult. Day 1, 32 month, N=2.

(−76.492.2 mV) through 3 days post EC, while young-adult muscle cells were notdifferent from controls by 2 days post exercise (Fig. 1). Aged muscles recovered tonormal values (−82.491.1 mV) and were not different from control by 4 daysfollowing EC.

3.2. Resting membrane potential following a second exposure to EC

The RMPs measured in muscle cells from young-adult rats were significantly lessdepolarized (−76.592.0) immediately (1 h) following a second exposure to ECcompared to those recorded after the initial exposure (D=5.1 mV) (Figs. 1 and 2).The RMPs were, however, still significantly depolarized compared to control valuesin the young-adult muscles. The RMPs in young-adult rats recovered to controlvalues (−83.891.4 mV) by 1 day following the second exposure to EC,compared to 2 days following the initial exposure (Figs. 1 and 2). Aged musclesfollowing a second exposure to EC were also significantly less depolarized (−71.391.5 mV) compared to those recorded after the initial exposure (D=3.5 mV)(Figs. 1 and 2). Aged muscles were significantly depolarized compared to theircontrols and compared to the values recorded in young-adult muscles followingEC (Figs. 1 and 2). Aged muscles remained significantly depolarized (−78.892.9mV) compared to control through 3 days following the second exposure toEC (Fig. 2).


3.3. Resting membrane potential following a single no6el exposure to EC in thepresence of streptomycin

Immediately following a single novel exposure to EC in the presence of thenon-specific SAC blocker streptomycin, young-adult muscles were significantly lessdepolarized (−79.191.35 mV) than without streptomycin treatment, but were stillsignificantly depolarized compared to control. The RMPs recovered to near normalvalues (−81.990.9 mV) and were not different from control by 1 day followingthe streptomycin protected exposure to EC (Fig. 3) (McBride et al., 2000). Agedmuscles were significantly more depolarized (−71.192.3 mV) compared to young-adult muscles immediately following the streptomycin protected exposure to EC.Although still statistically different from controls, aged muscles were near controlvalues by 3 days post EC in the presence of streptomycin (−80.293.3 mV)(Fig. 3).

3.4. Resting membrane potential following a single no6el exposure to EC in-6itroand in-6itro in the presence of Gd3+

The RMPs measured in muscle cells from young-adult rats were significantlydepolarized (−72.291.0 mV) compared to controls (−82.091.0 mV) immedi-

Fig. 3. Means9SD of RMP recorded from control and exercised TA (in vivo) after a single exposureto eccentric contractions in the presence of streptomycin blockade of SAC. Streptomycin treatmentbegan 6 days prior to the EC and continued until the recording were made. Each mean value representsat least four muscles with recordings from at least 25 fibers/muscle, unless otherwise indicated. Controlvalues are represented by the initial starting point. Measurements made at day 0 were recorded within1–2 h after exercise. Dashed lines and diamonds are aged muscles, solid lines and squares are youngadult muscles. * Significantly different (PB0.05) from mean RMP of contralateral control.† Significantly different (PB0.05) from mean RMP of young adult. Day 2, 32 month, N=2.


Fig. 4. Means9SD of RMP recorded from control and exercised TA (in vitro) immediately (1–2 h)after either a single exposure to EC (panel A), or after a fourth exposure to EC (panel B). Each meanvalue represents at least four muscles with recordings from at least 20 fibers/muscle. Plain bars representmean RMP before Gd3+, and black bars represent mean RMP after Gd3+ treatment. * Significantlydifferent (PB0.05) from mean RMP of aged muscles. Significantly different (PB0.05) from meanRMP of matched untreated muscles. † Significantly different (PB0.05) from mean RMP of agedmatched single EC muscles.

ately (1 h) following EC when measured in-vitro. The addition of Gd3+

to the bathing medium resulted in a significant repolarization (−76.791.8 mV), although it was still significantly depolarized compared tocontrol (McBride et al., 2000). The RMPs measured in muscle cells fromaged rats were also significantly depolarized (−69.790.5 mV) compared tocontrol (−82.291.3 mV) immediately (1 h) following EC when measured in-vitro. The addition of Gd3+ to the bathing medium did not result in a sig-nificant repolarization (−70.391.2 mV), as observed in the young-adult muscles(Fig. 4).

3.5. Resting membrane potential following four exposures to EC in-6itro andin-6itro in the presence of Gd3+

When young-adult muscles were exposed to four bouts of EC one week apart, theRMPs measured in-vitro were significantly less depolarized (−76.990.8 mV) thanfollowing a single exposure. The addition of Gd3+ to the bathing medium resultedin a significant repolarization (81.391.0 mV), and was not different from controlin-vitro RMPs (Fig. 4). Aged muscles exposed to four bouts of EC were also foundto be significantly less depolarized (−72.991.3 mV) in-vitro compared to a singleexposure. The addition of Gd3+ to the bathing medium did not produce asignificant repolarization (−72.691.3 mV) as observed in the young-adult muscles(Fig. 4).


4. Discussion

A novel exposure to eccentric contractions (EC) produced a significantly largerand more prolonged depolarization in the RMPs of aged muscles than has beenpreviously reported in young-adult muscles (McBride et al., 2000). In young-adultmuscles it was determined that blocking the SAC with the non-specific SAC blockerGd3+ in-vitro could eliminate approximately half of the depolarization followingEC. It is speculated that the remaining depolarization not eliminated by SACblockade is due to sarcolemmal damage produced by the mechanical strain of EC(Clarkson and Tremblay, 1988a; McNeil and Khakee, 1992). In-vitro treatment ofaged muscles with Gd3+ following EC did not result in a significant repolarizationas observed in the young-adult muscles (Fig. 4). This would indicate that themajority of the depolarization occurs via some mechanisms other than the openingof SAC, presumably a more extensive sarcolemmal injury. An increase in sarcolem-mal damage in aged human muscle following EC is not supported by increases inserum creatine kinase (CK) levels beyond that observed in young subjects (Clarksonand Dedrick, 1988b; Manfredi et al., 1991). There is some question as to theaccuracy of serum CK for quantifying muscle damage, and the conductance of ionssuch as Na+ could be affected much differently than CK. An increase in damageto the sarcolemma may explain the prolonged time course for the recovery ofRMPs back to normal values following EC in aged muscles. The increasedsarcolemmal damage may also be related to the prolonged recovery of contractilefunction following EC in aged muscle (Brooks and Faulkner, 1990; McBride et al.,1995). Even though the time course for maximum depolarization precedes the timecourse for the maximum loss in contractile force, it may serve as an early signal forcellular events leading to a loss in contractile function. The reduced recovery of theRMPs with SAC blockade following EC supports the hypothesis of fewer func-tional SAC in aged muscle.

Blocking the SAC with streptomycin in-vivo prior to the first exposure to ECprevented a significant amount of the depolarization, and resulted in a more rapidrecovery in young-adult muscles (Fig. 3). Aged muscles did not exhibit the sameprotective effect of the RMPs with SAC blockade (Fig. 3). This finding alsosupports the hypothesis that the majority of depolarization in aged musclesfollowing EC is the result of something other than the opening of SAC, such assarcolemmal damage.

The nonspecific permeability changes attributed to membrane damage are re-duced with repeated exposures to EC (Clarkson and Tremblay, 1988a; McBride etal., 2000). The RMPs of young-adult and aged muscles measured in-vitro immedi-ately following a second and fourth exposure to EC were significantly less depolar-ized than following the initial exposure (Figs. 2 and 4). This adaptive or repeatedbout effect following multiple exposures to EC has been observed previously(Clarkson and Dedrick, 1988b; Sacco and Jones, 1992; McBride et al., 1995). Theadaptive response is characterized by a decrease in sarcomere damage and reduc-tion in the amount of contractile force impairment normally observed following anacute exposure to EC. The RMPs in young-adult muscles can be significantly


repolarized after the initial exposure, and completely repolarized to control valuesafter the fourth exposure to EC, by the addition of Gd3+ to the bathing medium(Fig. 4). Aged muscles did not repolarize following Gd3+ treatment after the initialexposure to EC and remained unaffected following the fourth exposure (Fig. 4).The modest adaptive response of aged muscles measured after the fourth exposureto EC is not repolarized any further toward control values as observed in theyoung-adult muscles (Fig. 4). It thus appears that the majority of membranedepolarization in aged muscles following repeated exposures to EC continues to bethe result of sarcolemmal damage and not the opening of SAC. From these data itappears that aged muscles either have a reduced number of SAC, or the SAC arenot functional, or they are modified in such a way that they are not sensitive theSAC blocker Gd3+.

The exact function of SAC is unclear, but they seem to play a role in the pathwayfor transduction of mechanical stimuli in cells. In both cardiac and smooth musclecells SAC have been linked to stretch induced cell growth (Kent et al., 1989;Komuro et al., 1996), and they may play a similar role in skeletal muscles as well(Vandenburgh, 1992; McBride et al., 2000). Both cardiac and skeletal musclerespond similarly to a mechanical stretch with an increase in gene expression, anincrease in protein synthesis, and cellular hypertrophy (Kent et al., 1989; Goldspinket al., 1992; Sadoshima and Izumo, 1993; Williams and Neufer, 1996). Na+ influxthrough SAC is reported to stimulate protein synthesis and cell growth in mam-malian myocardium (Kent et al., 1989), but has yet to be directly established inskeletal muscle. It is reasonable to hypothesize that SAC may play a role insignaling the cellular events that result in the eventual adaptive response of muscleto EC. This is supported by previous observations in young-adult muscles that weretreated with streptomycin prior to the initial exposure to EC (McBride et al., 2000).When treated with streptomycin, SAC are blocked during the initial exposure, andthe adaptive response is significantly compromised. Following the initial exposurethe animals were taken off streptomycin and the muscles were allowed to recoverbefore a second exposure this time with no SAC blockade (McBride et al., 2000).The muscles subsequently responded to a second exposure to EC as if it were theinitial. In effect streptomycin blockade during the initial exposure prevented theadaptive response from occurring. This pattern of limited adaptation in SACblocked muscles from young-adult muscles is similar to what was observed inuntreated aged muscles following their second exposure to EC. These data suggestthat functional SAC contribute to the adaptive process, which most likely includesthe integration of a number of cellular events. The reduced capacity for agedmuscles to adapt to EC may then be the result of a reduced population offunctional SAC.

Despite the differences observed in membrane depolarization and the hypothe-sized differences in SAC, aged muscles are capable of responding positively to highresistance strength training programs (Frontera et al., 1988; Brown, 1989; Klita-gaard et al., 1989; Brown et al., 1990, 1992). It is yet to be determined whether ornot the hypothesized reduction in SAC contributes to the loss in muscle functionwith aging, or results in a reduced capacity of aged muscles to respond positivelyspecifically to eccentric training.


5. Conclusion

From the present data it is clear that aged muscles experience a significantlygreater depolarization of the RMP following EC, and the RMP takes longer torepolarize to control values compared to young-adult muscles. Aged musclesexposed to a second EC demonstrate a significantly reduced adaptive response, andexperience a significantly greater depolarization of the RMP compared to young-adult muscles. Aged muscles do not repolarize following EC in the presence of theSAC blockers streptomycin or Gd3+. This indicates that depolarization is due tosomething other than the opening of SAC as observed in young-adult muscles. It istherefore speculated that aged muscles have fewer functional SAC, and this deficitmay contribute to the aged muscles reduced ability to adapt to EC.

Acknowledgements

California State University, Bakersfield, Foundation. NIA Pilot Project. Theauthor would also like to thank Dr Annette Halpern-Hinds for editorial assistance.

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