Christopher P. Ingalls

Excitation-contraction uncoupling: major role in contraction-induced muscle injury.

WARREN, G.L., C.P. INGALLS, D.A. LOWE, and R.B. ARMSTRONG. Excitation-contraction uncoupling: major role in contraction-induced muscle injury. Exerc. Sports Sci. Rev., Vol. 29, No. 2, pp. 82-87, 2001. The mechanisms that account for the strength loss after contraction-induced muscle injury remain controversial. We present data showing that (1) most of the early strength loss results from a failure of excitation-contraction coupling and (2) a slow loss of contractile protein in the days after injury prolongs the recovery time.

Decreased EMG median frequency during a second bout of eccentric contractions

PURPOSE Others have reported preferential recruitment of fast motor units in muscles during performance of eccentric contractions and there is evidence that fast muscle fibers are more susceptible to eccentric contraction-induced injury. We tested the hypothesis that during a second bout of maximal eccentric contractions 1 wk after the first, there would be a reduction in the electromyographic (EMG) median frequency (MF) with minimal change in the EMG root-mean-square (RMS), indicating greater reliance on slower motor units. This could provide an explanation for the enhanced resistance to eccentric contraction-induced injury after a single bout of eccentric exercise. METHODS Human subjects performed 50 maximal voluntary eccentric (N = 10) or concentric (N = 10) contractions of the anterior crural muscles on two occasions separated by 1 wk. To determine whether MF changes during the second bout could be a consequence of injury to fibers in fast motor units, the anterior crural muscles of mice were electrically stimulated to perform 50 maximal eccentric (N = 10) or concentric (N = 9) contractions on two occasions separated by 1 wk. In both the humans and mice, torque production and tibialis anterior muscle RMS and MF were measured during the two exercise bouts. RESULTS In human tibialis anterior muscle, MF was 30% lower (P < 0.01) during the second eccentric bout although RMS was the same. In the mice, RMS and MF were unchanged at any time after the first eccentric bout despite torque deficits similar to those observed in the humans. CONCLUSIONS The data indicate that with repetition of maximal voluntary eccentric contractions, there is an increased activation of slow motor units and a concomitant decrease in activation of fast units.

Dissociation of force production from MHC and actin contents in muscles injured by eccentric contractions

The primary purpose of this study was to determine the relationship between myosin heavy chain (MHC) and actin contents and maximum isometric tetanic force (Po) in mouse extensor digitorum longus (EDL) muscles following eccentric contraction-induced injury. Po and protein contents were measured in injured (n=80) and contralateral control (n = 80) EDL muscles at the following time points after in vivo injury: sham, 0, 0.25, 1, 3, 5, 14, and 28 days. Po was reduced by 37 ± 2.3% to 49 ± 3.8% (p ≤ 0.05), while MHC and actin contents were unaltered from 0 to 3 days after injury. Whereas Po partially recovered between 3 and 5 days (from −49 ± 3.8% to −35 ± 3.6%), MHC and actin contents in the injured muscles declined by 19 ± 4.9% and 20 ± 5.3%, respectively, by 5 days compared with control muscles. Decrements in Po were similar to the reductions in MHC and actin contents at 14 (∼24%) and 28 (∼11%) days. Evaluation of myofibrillar and soluble protein fractions indicated significant reductions in the content of major proteins at 5 and 14 days. Immunoblots of heat shock protein 72 revealed elevations starting at 0.25 days, peaking during 1–3 days, and declining after 5days. These findings indicate that decreased contractile protein content is not related to the initial decrease in Po. However, decreased MHC and actin contents could account for 58% of the Po reduction at 5 days, and for nearly all the decrements in Po from 14 to 28 days.

Uncoupling of in vivo torque production from EMG in mouse muscles injured by eccentric contractions

1 The main objective of this study was to determine whether eccentric contraction‐induced muscle injury causes impaired plasmalemmal action potential conduction, which could explain the injury‐induced excitation‐contraction coupling failure. Mice were chronically implanted with stimulating electrodes on the left common peroneal nerve and with electromyographic (EMG) electrodes on the left tibialis anterior (TA) muscle. The left anterior crural muscles of anaesthetized mice were stimulated to perform 150 eccentric (ECC) (n= 12 mice) or 150 concentric (CON) (n= 11 mice) contractions. Isometric torque, EMG root mean square (RMS) and M‐wave mean and median frequencies were measured before, immediately after, and at 1, 3, 5 and 14 days after the protocols. In parallel experiments, nicotinic acetylcholine receptor (AChR) concentration was measured in TA muscles to determine whether the excitation failure elicited a denervation‐like response. 2 Immediately after the ECC protocol, torque was reduced by 47–89%, while RMS was reduced by 9–21%; the RMS decrement was not different from that observed for the CON protocol, which did not elicit large torque deficits. One day later, both ECC and CON RMS had returned to baseline values and did not change over the next 2 weeks. However, torque production by the ECC group showed a slow recovery over that time and was still depressed by 12–30% after 2 weeks. M‐wave mean and median frequencies were not affected by performance of either protocol. 3 AChR concentration was elevated by 79 and 368% at 3 and 5 days, respectively, after the ECC protocol; AChR concentration had returned to control levels 2 weeks after the protocol. At the time of peak AChR concentration in the ECC protocol muscles (i.e. 5 days), AChR concentration in CON protocol muscles was not different from the control level. 4 In conclusion, these data demonstrate no major role for impaired plasmalemmal action potential conduction in the excitation‐contraction coupling failure induced by eccentric contractions. Additionally, a muscle injured by eccentric contractions shows a response in AChR concentration similar to a transiently denervated muscle.

Skeletal Muscle Lipid Peroxidation and Insulin Resistance in Humans

OBJECTIVE The relationships among skeletal muscle lipid peroxidation, intramyocellular lipid content (IMCL), and insulin sensitivity were evaluated in nine insulin-sensitive (IS), 13 insulin-resistant (IR), and 10 adults with type 2 diabetes (T2DM). DESIGN Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp [glucose disposal rate (GDR)]. Lipid peroxidation was assessed by 4-hydroxynonenal (HNE)-protein adducts and general oxidative stress by protein carbonyl content. All patients were sedentary. RESULTS Protein-HNE adducts were elevated 1.6-fold in T2DM compared with IS adults, whereas IR showed intermediate levels of HNE-modified proteins. Protein-HNE adducts correlated with GDR, waist circumference, and body mass index. IMCL was increased by 4.0- and 1.9-fold in T2DM and IR patients, respectively, compared with IS, and was correlated with GDR and waist circumference but not BMI. Protein carbonyls were not different among groups and did not correlate with any of the measured variables. Correlations were detected between IMCL and protein-HNE. CONCLUSION Our data show for the first time that skeletal muscle protein-HNE adducts are related to the severity of insulin resistance in sedentary adults. These results suggest that muscle lipid peroxidation could be involved in the development of insulin resistance.

FKBP12 deficiency reduces strength deficits after eccentric contraction-induced muscle injury.

Strength deficits associated with eccentric contraction-induced muscle injury stem, in part, from excitation-contraction uncoupling. FKBP12 is a 12-kDa binding protein known to bind to the skeletal muscle sarcoplasmic reticulum Ca2+ release channel [ryanodine receptor (RyR1)] and plays an important role in excitation-contraction coupling. To assess the effects of FKBP12 deficiency on muscle injury and recovery, we measured anterior crural muscle (tibialis anterior and extensor digitorum longus muscles) strength in skeletal muscle-specific FKBP12-deficient and wild-type (WT) mice before and after a single bout of 150 eccentric contractions, as well as before and after the performance of six injury bouts. Histological damage of the tibialis anterior muscle was assessed after injury. Body weight and peak isometric and eccentric torques were lower in FKBP12-deficient mice compared with WT mice. There were no differences between FKBP12-deficient and WT mice in preinjury peak isometric and eccentric torques when normalized to body weight, and no differences in the relative decreases in eccentric torque with a single or multiple injury bouts. After a single injury bout, FKBP12-deficient mice had less initial strength deficits and recovered faster (especially females) than WT mice, despite no differences in the degree of histological damage. After multiple injury bouts, FKBP12-deficient mice recovered muscle strength faster than WT mice and exhibited significantly less histological muscle damage than WT mice. In summary, FKBP12 deficiency results in less initial strength deficits and enhanced recovery from single (especially females) and repeated bouts of injury than WT mice.

Muscle injury after low-intensity downhill running reduces running economy.

Abstract Baumann, CW, Green, MS, Doyle, JA, Rupp, JC, Ingalls, CP, and Corona, BT. Muscle injury after low-intensity downhill running reduces running economy. J Strength Cond Res 28(5): 1212–1218, 2014—Contraction-induced muscle injury may reduce running economy (RE) by altering motor unit recruitment, lowering contraction economy, and disturbing running mechanics, any of which may have a deleterious effect on endurance performance. The purpose of this study was to determine if RE is reduced 2 days after performing injurious, low-intensity exercise in 11 healthy active men (27.5 ± 5.7 years; 50.05 ± 1.67 V[Combining Dot Above]O2peak). Running economy was determined at treadmill speeds eliciting 65 and 75% of the individuals peak rate of oxygen uptake (V[Combining Dot Above]O2peak) 1 day before and 2 days after injury induction. Lower extremity muscle injury was induced with a 30-minute downhill treadmill run (6 × 5 minutes runs, 2 minutes rest, −12% grade, and 12.9 km·h−1) that elicited 55% V[Combining Dot Above]O2peak. Maximal quadriceps isometric torque was reduced immediately and 2 days after the downhill run by 18 and 10%, and a moderate degree of muscle soreness was present. Two days after the injury, steady-state V[Combining Dot Above]O2 and metabolic work (V[Combining Dot Above]O2 L·km−1) were significantly greater (4–6%) during the 65% V[Combining Dot Above]O2peak run. Additionally, postinjury V[Combining Dot Above]CO2, VE and rating of perceived exertion were greater at 65% but not at 75% V[Combining Dot Above]O2peak, whereas whole blood-lactate concentrations did not change pre-injury to postinjury at either intensity. In conclusion, low-intensity downhill running reduces RE at 65% but not 75% V[Combining Dot Above]O2peak. The results of this study and other studies indicate the magnitude to which RE is altered after downhill running is dependent on the severity of the injury and intensity of the RE test.

Differential effects of temperature on contractile behavior in isolated frog skeletal muscle

1. The thermal dependence of contractile behavior at different stimulation frequencies was investigated in isolated frog sartorius muscles. 2. Increasing incubation temperature (10-30 degrees C) produced decreases in Pt (43.7%) and P15 (70.3%), and an increase in Po (26.0%). 3. Thermal ratios (R10) calculated for Pt, P15 and Po indicated high thermal dependence at lower temperatures (10-20 degrees C; 0.60, 0.44 and 1.38, respectively) but relative thermal independence at higher temperatures (20-30 degrees C; 0.95, 0.75 and 0.95, respectively). 4. Contractile ratios (Pt/Po and P15/Po) decreased with increased temperature (10-30 degrees C; 56.3% and 76.0%, respectively). 5. Thermal ratios (R20) calculated for peak tension at different stimulation frequencies demonstrated high thermal dependence at the lower frequencies (10-30 pps, 0.46-0.48) and decreasing dependence at higher frequencies (40-50 pps, 0.69-0.82).