Strength, skeletal muscle composition, and enzyme activity in multiple sclerosis

Kent-Braun, J. A., A. V. Ng, M. Castro, M. W. Weiner, D. Gelinas, G. A. Dudley, and R. G. Miller. Strength, skeletal musclecomposition and enzyme activity in multiple sclerosis. J. Appl. Physiol. 83(6):1998-2004, 1997.This study examined functional, biochemical, andmorphological characteristics of skeletal muscle in nine multiplesclerosis (MS) patients and eight healthy controls in an effort toascertain whether intramuscular adaptations could account for excessivefatigue in this disease. Analyses of biopsies of the tibialis anteriormuscle showed that there were fewer type I fibers (66 ± 6 vs. 76 ± 6%), and that fibers of all types were smaller (average26%) and had lower succinic dehydrogenase (SDH; average40%) and SDH/-glycerol-phosphate dehydrogenase (GPDH) butnot GPDH activities in MS vs. control subjects, suggesting that musclein this disease is smaller and relies more on anaerobic thanaerobic-oxidative energy supply than does muscle of healthyindividuals. Maximal voluntary isometric force fordorsiflexion was associated with both average fiber cross-sectionalarea (r = 0.71, P = 0.005) and muscle fat-free cross-sectional area by magnetic resonance imaging(r = 0.80, P < 0.001). Physical activity,assessed by accelerometer, was associated with average fiber SDH/GPDH(r = 0.78, P = 0.008). There was a tendency forsymptomatic fatigue to be inversely associated with average fiber SDHactivity (r = 0.57,P = 0.068). The results of thisstudy suggest that the inherent characteristics of skeletal musclefibers per se and of skeletal muscle as a whole are altered in thedirection of disuse in MS. They also suggest that changes in skeletalmuscle in MS may significantly affect function.

     

Substance P Enhances Desensitization of the Nicotinic Response in Bovine Chromaffin Cells but Enhances Secretion upon Removal

A fundamental process in neurosecretion is desensitization, or a declining response to a stimulus. The response of chromaffin cells to continuous nicotinic stimulation, secretion of catecholamines, desensitizes within a few minutes. The neuropeptide substance P (SP) has been reported to prevent desensitization in culture dish experiments and to enhance desensitization in patch clamp studies. In the present study, these contradictory responses have been demonstrated and the apparent contradictions resolved. We have measured catecholamine secretion by on-line electrochemical detection in a constant-pressure flow system. Isolated chromaffin cells cultured on quartz plates were stimulated with the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP) in the presence and absence of SP. SP inhibited secretion and increase the rate of desensitization compared with stimulation by DMPP alone. However, when the cells were stimulated a second time with DMPP alone immediately after 5-min stimulation with SP + DMPP, the rate of desensitization was markedly lower than the control. Removal of SP after a desensitizing stimulation with SP + DMPP caused a slow secondary release of catecholamine in response to the continued stimulation with DMPP. The kinetic analysis of the secretory response shows that the primary response to SP is enhanced desensitization, but that upon removal of SP the response to DMPP desensitizes less rapidly. We suggest that SP protects some receptors from nicotinic desensitization while holding them in an inactive state, and that upon removal of SP these receptors can slowly respond to DMPP.     

Central and peripheral contributions to muscle fatigue in humans during sustained maximal effort

The purpose of this study was to estimate the relative contributions of central and peripheral factors to the development of human muscle fatigue. Nine healthy subjects [five male, four female; age = 30 (2) years, mean (SE)] sustained a maximum voluntary isometric contraction (MVC) of the ankle dorsiflexor muscles for 4 min. Fatigue was quantitated as the fall in MVC. Three measures of central activation and one measure of peripheral activation (compound muscle action potential, CMAP) were made using electromyography (EMG) and electrical stimulation. Measures of intramuscular metabolism were made using magnetic resonance spectroscopy. After exercise, MVC and electrically stimulated tetanic contraction (50 Hz, 500 ms) forces were 22.2 (3.7)% and 37.3 (7.1)% of pre-exercise values, respectively. The measures of central activation suggested some central fatigue during exercise: (1) the central activation ratio [MVC/(MVC + superimposed tetanic force)] fell from 0.94 (0.03) to 0.78 (0.09), (2) the MVC/tetanic force ratio fell from 2.3 (0.7) to 1.3 (0.7), and (3) the integral of the EMG (iEMG) signal decreased to 72.6 (9.1)% of the initial value, while the CMAP amplitude was unchanged. Intramuscular pH was associated by regression with the decline in MVC force (and therefore fatigue) and iEMG. The results indicate that central factors, which were not associated with altered peripheral excitability, contributed approximately 20% to the muscle fatigue developed, with the remainder being attributable to intramuscular (i.e., metabolic) factors. The association between pH and iEMG is consistent with proton concentration as a feedback mechanism for central motor drive during maximal effort.     

Effect of old age on human skeletal muscle force-velocity and fatigue properties

It is generally accepted that the muscles of aged individuals contract with less force, have slower relaxation rates, and demonstrate a downward shift in their force-velocity relationship. The factors mediating age-related differences in skeletal muscle fatigue are less clear. The present study was designed to test the hypothesis that age-related shifts in the force-velocity relationship impact the fatigue response in a velocity-dependent manner. Three fatigue protocols, consisting of intermittent, maximum voluntary knee extension contractions performed for 4 min, were performed by 11 young (23.5 ± 0.9 yr, mean ± SE) and 10 older (68.9 ± 4.3) women. The older group fatigued less during isometric contractions than the young group (to 71.1 ± 3.7% initial torque and 59.8 ± 2.5%, respectively; P = 0.02), while the opposite was true during contractions performed at a relatively high angular velocity of 270°·s(-1) (old: 28.0 ± 3.9% initial power, young: 52.1 ± 6.9%; P < 0.01). Fatigue was not different (P = 0.74) between groups during contractions at an intermediate velocity, which was selected for each participant based on their force-velocity relationship. There was a significant association between force-velocity properties and fatigue induced by the intermediate-velocity fatigue protocol in the older (r = 0.72; P = 0.02) and young (r = 0.63; P = 0.04) groups. These results indicate that contractile velocity has a profound impact on age-related skeletal muscle fatigue resistance and suggest that changes in the force-velocity relationship partially mediate this effect.     

Neural and metabolic mechanisms of excessive muscle fatigue in maintenance hemodialysis patients

Dialysis patients have severe exercise limitations related to metabolic disturbances, but muscle fatigue has not been well studied in this population. We investigated the magnitude and mechanisms of fatigue of the ankle dorsiflexor muscles in patients on maintenance hemodialysis. Thirty-three dialysis patients and twelve healthy control subjects performed incremental isometric dorsiflexion exercise, beginning at 10% of their maximal voluntary contraction (MVC) and increasing by 10% every 2 min. Muscle fatigue (fall of MVC), completeness of voluntary activation, and metabolic responses to exercise were measured. Before exercise, dialysis subjects exhibited reduced strength and impaired peripheral activation (lower compound muscle activation potential amplitude) but no metabolic perturbation. During exercise, dialysis subjects demonstrated threefold greater fatigue than controls with evidence of central activation failure but no change in peripheral activation. All metabolic parameters were significantly more perturbed at end exercise in dialysis subjects than in controls, including lower phosphocreatine (PCr) and pH, and higher P(i), P(i)/PCr, and H(2)PO(4)(-). Oxidative potential was markedly lower in patients than in controls [62.5 (SD 27.2) vs. 134.6 (SD 31.7), P < 0.0001]. Muscle fatigue was negatively correlated with oxidative potential among dialysis subjects (r = -0.52, P = 0.04) but not controls. Changes in central activation ratio were also correlated with muscle fatigue in the dialysis subjects (r = 0.59, P = 0.001) but not the controls. This study provides new information regarding the excessive muscular fatigue of dialysis patients and demonstrates that the mechanisms of this fatigue include both intramuscular energy metabolism and central activation failure.     

Skeletal muscle contractile and noncontractile components in young and older women and men.

To examine the influences of age, gender, and habitual physical activity level on human skeletal muscle composition, we developed a relatively simple magnetic resonance imaging method for the quantitation of leg anterior compartment contractile and noncontractile content. We studied 23 young (11 women and 12 men, 26-44 yr old) and 21 older (10 women and 11 men, 65-83 yr old) healthy adults. Analysis was by two-factor (age, gender) ANOVA. Physical activity, quantitated by three-dimensional accelerometer worn about the waist for 1 wk, was not different between groups. Men had larger contractile and noncontractile cross-sectional areas (cm(2)) than women, with no gender effect on percent noncontractile area. Young subjects had larger contractile areas and smaller absolute (cm(2)) and relative (percent total) noncontractile areas than older subjects. There was a significant linear relationship between physical activity and percent noncontractile area in older (r = -0.68, P = 0.002) but not young subjects. These data demonstrate a more than twofold increase in the noncontractile content of locomotor muscles in older adults and provide novel support for physical activity as a modulator of this age-related change in muscle composition.     

Postmaximal contraction blood volume responses are blunted in obese and type 2 diabetic subjects in a muscle-specific manner

The purpose of this study was to determine whether there are differences in postisometric contraction blood volume and oxygenation responses among groups of type 2 diabetes mellitus (T2DM), obese, and lean individuals detectable using MRI. Eight T2DM patients were individually matched by age, sex, and race to non-T2DM individuals with similar body mass index (obese) and lean subjects. Functional MRI was performed using a dual-gradient-recalled echo, echo-planar imaging sequence with a repetition time of 1 s and at two echo times (TE = 6 and 46 ms). Data were acquired before, during, and after 10-s isometric dorsiflexion contractions performed at 50 and 100% of maximal voluntary contraction (MVC) force. MRI signal intensity (SI) changes from the tibialis anterior and extensor digitorum longus muscles were plotted as functions of time for each TE. From each time course, the difference between the minimum and the maximum postcontraction SI (ΔSI) were determined for TE = 6 ms (ΔSI(6)) and TE = 46 ms (ΔSI(46)), reflecting variations in blood volume and oxyhemoglobin saturation, respectively. Following 50% MVC contractions, the mean postcontraction ΔSI(6) values were similar in the three groups. Following MVC only, and in the EDL muscle only, T2DM and obese participants had ～56% lower ΔSI(6) than the lean individuals. Also following MVC only, the ΔSI(46) response in the EDL was lower in T2DM subjects than in lean individuals. These data suggest that skeletal muscle small vessel impairment occurs in T2DM and body mass index-matched subjects, in muscle-specific and contraction intensity-dependent manners.     

Contractile and non-contractile tissue volume and distribution in ankle muscles of young and older adults

Magnetic resonance imaging (MRI) enables accurate in vivo quantification of human muscle volumes, which can be used to estimate subject-specific muscle force capabilities. An important consideration is the amount of contractile and non-contractile tissue in the muscle compartment, which will influence force capability. We quantified age-related differences in the proportion and distribution of contractile and non-contractile tissue in the dorsiflexor and plantar flexor (soleus, and medial and lateral heads of gastrocnemius) muscles, and examined how well these volumes can be estimated from single MRI cross-sections. Axial MRIs of the left leg for 12 young (mean age 27 years) and 12 older (72 years) healthy, active adults were used to compute muscle volumes. Contractile tissue distribution along the leg was characterized by mathematical functions to allow volume prediction from single-slice cross-sectional area (CSA) measurements. Compared to young, older adults had less contractile volume and a greater proportion of non-contractile tissue. In both age groups the proportion of non-contractile tissue increased distally, with the smallest proportion near the maximum compartment CSA. A single CSA measurement predicted contractile volume with 8-11% error, with older adults in the higher end of this range. Using multiple slices improved volume estimates by roughly 50%, with average errors of about 3-4%. These results demonstrate significant age-related differences in non-contractile tissue for the dorsi- and plantar-flexor muscles. Although estimates of contractile volume can be obtained from single CSA measurements, multiple slices are needed for increased accuracy due to inter-individual variations in muscle volume and composition.     

Human skeletal muscle responses vary with age and gender during fatigue due to incremental isometric exercise.

The purpose of this study was to compare the magnitude and mechanisms of ankle dorsiflexor muscle fatigue in 20 young (33 +/- 6 yr, mean +/- SD) and 21 older (75 +/- 6 yr) healthy men and women of similar physical activity status. Noninvasive measures of central and peripheral (neuromuscular junction, sarcolemma) muscle activation, muscle contractile function, and intramuscular energy metabolism were made before, during, and after incremental isometric exercise. Older subjects fatigued less than young (P < 0.01); there was no effect of gender on fatigue (P = 0.24). For all subjects combined, fatigue was modestly related to preexercise strength (r = 0.49, P < 0.01). Neither central (central activation ratio) nor peripheral (compound muscle action potential) activation played a significant role in fatigue in any group. During exercise, intracellular concentrations of P(i) and H(2)PO increased more and pH fell more in young compared with older subjects (P < 0.01) and in men compared with women (P < 0.01). These varied metabolic responses to exercise suggest a greater reliance on nonoxidative sources of ATP in young compared with older subjects and in men compared with women. These results suggest that the mechanisms of fatigue vary with age and gender, regardless of whether differences in the magnitude of fatigue are observed.     

Specific strength and voluntary muscle activation in young and elderly women and men.

The extents to which decreased muscle size or activation are responsible for the decrease in strength commonly observed with aging remain unclear. Our purpose was to compare muscle isometric strength [maximum voluntary contraction (MVC)], cross-sectional area (CSA), specific strength (MVC/CSA), and voluntary activation in the ankle dorsiflexor muscles of 24 young (32 +/- 1 yr) and 24 elderly (72 +/- 1 yr) healthy men and women of similar physical activity level. Three measures of voluntary muscle activation were used: the central activation ratio [MVC/(MVC + superimposed force)], the maximal rate of voluntary isometric force development, and foot tap speed. Men had higher MVC and CSA than did women. Young men had higher MVC compared with elderly men [262 +/- 19 (SE) vs. 197 +/- 22 N, respectively], whereas MVC was similar in young and elderly women (136 +/- 15 vs. 149 +/- 16 N, respectively). CSA was greater in young compared with elderly subjects. There was no age-related impairment of specific strength, central activation ratio, or the rate of voluntary force development. Foot tap speed was reduced in elderly (34 +/- 1 taps/10 s) compared with young subjects (47 +/- 1 taps/10 s). These results suggest that isometric specific strength and the ability to fully and rapidly activate the dorsiflexor muscles during a single isometric contraction were unimpaired by aging. However, there was an age-related deficit in the ability to perform rapid repetitive dynamic contractions.