Preconditioning contractions prevent Ca2+-dependent proteolysis of STAC3 and prolonged force depression after eccentric contractions

Preconditioning contractions (PCs) have been shown to markedly improve recovery from force depression after damaging eccentric contractions (ECCs). Here, we examined the mechanism underlying the effects of PCs with special focus on the SH3 and cysteine rich domain 3 (STAC3) that is essential for the transduction of action potential to the Ca2+ release from the sarcoplasmic reticulum. Rat medial gastrocnemius (MG) muscles were removed immediately (REC0), 1 d (REC1), and 4 d (REC4) after exposure to 100 repeated in vivo damaging ECCs. PCs with 10 repeated nondamaging ECCs were applied 2 d before the damaging ECCs. Damaging ECCs induced in vivo isometric torque depression at 50 and 100 Hz stimulation frequencies at REC1 and REC4, which was accompanied by a significant reduction in the amount of STAC3, an activation of calpain 1, and an increased number of Evans Blue dye positive fibers in MG muscles. Importantly, PCs attenuated all these deleterious alterations induced by damaging ECCs. Moreover, mechanistic experiments performed on normal muscle tissue exposed to various concentration of Ca2+ showed a Ca2+-dependent proteolysis of STAC3, which was prevented by calpain inhibitor MDL-28170. In conclusion, PCs improve recovery from force depression after damaging ECCs, presumably by inhibiting the loss of STAC3 due to the increased permeability of cell membrane and subsequent activation of calpain 1.

Preconditioning contractions prevent prolonged force depression and Ca2+-dependent proteolysis of STAC3 after damaging eccentric contractions

Preconditioning contractions (PCs) have been shown to markedly improve recovery from eccentric contractions (ECCs)-induced force depression. We here examined the mechanism behind the effects of PCs with focusing on the SH3 and cysteine rich domain 3 (STAC3) that is essential for coupling membrane depolarization to Ca2+ release from the sarcoplasmic reticulum. Rat medial gastrocnemius (MG) muscles were excised immediately (REC0), 1 day (REC1), and 4 days (REC4) after exposure to 100 repeated damaging ECCs in vivo. PCs with 10 repeated non-damaging ECCs were applied 2 days before the damaging ECCs. Damaging ECCs induced in vivo isometric torque depression at 50 and 100 Hz stimulation frequencies, which was accompanied by a significant decrease in the amount of full-length STAC3, an activation of calpain 1, and an increased number of Evans Blue dye positive fibers in MG muscles at REC1 and REC4. Interestingly, PCs attenuated all these deleterious alterations induced by damaging ECCs. Moreover, mechanistic experiments performed on normal muscle samples exposed to various concentration of Ca2+ showed a Ca2+-dependent proteolysis of STAC3, which was prevented by calpain inhibitor MDL-28170. In conclusion, PCs may improve recovery from force depression after damaging ECCs, in part by inhibiting the loss of STAC3 due to the increased permeability of cell membrane and subsequent activation of calpain 1.

Maximal results with minimal stimuli: the fewest high-frequency pulses needed to measure or model prolonged low-frequency force depression in the dorsiflexors

Quantifying prolonged low-frequency force depression (PLFFD) with the gold-standard 1-s trains presents challenges so paired-pulses have been used. Owing to greater impairment of high-frequency doublet than tetanic torque, paired-pulses underestimate PLFFD. This study aimed to approximate the minimum number of high-frequency pulses needed to avoid such underestimation and assess the feasibility of modelling PLFFD from a limited number of experimental pulses. In 13 participants, a 1-s 10-Hz train and 100-Hz trains with 2, 4, 7, 12, 15, 25, 50, or 100 pulses were evoked before and after (15 min, 2, 4, and 7 d) eccentric exercise of the dorsiflexors. With ≤ 12 pulses, impairment of 100-Hz torque was greater than the 1-s train (P ≤ 0.05; e.g., 12 vs. 100 pulses at 4d: 97.8 ± 8.5% vs. 100.5 ± 8.2% baseline). Consequently, with ≤ 12 pulses, PLFFD was underestimated compared to the gold-standard measure (P ≤ 0.05; e.g., 12 vs. 100 pulse 10:100 Hz torque ratio at 4d: 86.8 ± 12.8% vs. 84.6 ± 13.5% baseline). Modelling reproduced 10:100 Hz ratios (PLFFD) with 95% limits of agreement of −13.6-16.7% of experimental values with ≥ 12 pulses. Our results indicate that a minimum of 13-25 100-Hz pulses are needed to accurately quantify PLFFD in the dorsiflexors. Although this may not be the minimum range for other muscles, a similar relationship with pulse number likely exists. Modelling may eventually provide an option to estimate PLFFD from experimental trains with relatively few pulses; however, further development is imperative to reduce variability.

Females and males do not differ for fatigability, muscle damage and magnitude of the repeated bout effect following maximal eccentric contractions

Unaccustomed eccentric (ECC) exercise induces muscle fatigue as well as damage and initiates a protective response to minimize impairments from a subsequent bout (i.e., repeated bout effect; RBE). It is uncertain if the sexes differ for neuromuscular responses to ECC exercise and the ensuing RBE. Twenty-six young adults (13 females) performed two bouts (four weeks apart) of 200 ECC maximal voluntary contractions (MVCs) of the dorsiflexors. Isometric (ISO) MVC torque and the ratio of ISO torque in response to low- vs. high-frequency stimulation (10:100Hz) were compared before and after (2-10min and 2, 4, and 7d) exercise. The decline in ECC and ISO MVC torque, and the 10:100Hz ratio following bout one did not differ between sexes (P > 0.05), with reductions from baseline of 31.5 ± 12.3, 24.1 ± 15.4, and 51.3 ± 12.2%, respectively. After bout two, the 10:100Hz ratio declined less (45.0 ± 12.4% from baseline) and ISO MVC torque recovered sooner compared to bout one but no differences between sexes were evident for the magnitude of the RBE (P > 0.05). These data suggest that fatigability with ECC exercise does not differ for the sexes and adaptations that mitigate impairments to calcium handling are independent of sex. NOVELTY BULLETS: • One bout of 200 maximal eccentric dorsiflexor contractions caused equivalent muscle fatigue and damage for females and males • The repeated bout effect observed after a second bout four weeks later also had no sex-related differences • Prolonged low-frequency force depression is promoted as an indirect measure of muscle damage in humans

The influence of training-induced sarcomerogenesis on the history dependence of force

ABSTRACTThe increase or decrease in isometric force following active muscle lengthening or shortening, relative to a reference isometric contraction at the same muscle length and level of activation, are referred to as residual force enhancement (rFE) and residual force depression (rFD), respectively. The purpose of these experiments was to investigate the trainability of rFE and rFD on the basis of serial sarcomere number (SSN) alterations to history-dependent force properties. Maximal rFE/rFD measures from the soleus and extensor digitorum longus (EDL) of rats were compared after 4 weeks of uphill or downhill running with a no-running control. SSN adapted to the training: soleus SSN was greater with downhill compared with uphill running, while EDL demonstrated a trend towards more SSN for downhill compared with no running. In contrast, rFE and rFD did not differ across training groups for either muscle. As such, it appears that training-induced SSN adaptations do not modify rFE or rFD at the whole-muscle level.

Inhibitory tendon-evoked reflex is attenuated in the torque-depressed isometric steady-state following active shortening

Residual torque depression (rTD) is the reduction in steady-state isometric torque following an active shortening contraction when compared with an isometric contraction at the same muscle length and activation level. We have shown that spinal excitability increases in the rTD state, yet the mechanisms remains unknown. Percutaneous electrical tendon stimulation was used to induce tendon-evoked inhibitory reflexes. We demonstrated that in the rTD state, reduced torque contributes to a reduction in inhibitory afferent feedback, which indicates that the history-dependent properties of muscle can alter spinal excitability and the voluntary control of submaximal contractions through changes in peripheral afferent feedback. Novelty Residual force depression is a basic property of skeletal muscle, which can influence spinal and supraspinal excitability via inhibitory reflex activity. Residual force depression alters the voluntary control of force.

Lower Ca2+ enhances the K+-induced force depression in normal and HyperKPP mouse muscles

Hyperkalemic periodic paralysis (HyperKPP) manifests as stiffness or subclinical myotonic discharges before or during periods of episodic muscle weakness or paralysis. Ingestion of Ca2+ alleviates HyperKPP symptoms, but the mechanism is unknown because lowering extracellular [Ca2+] ([Ca2+]e) has no effect on force development in normal muscles under normal conditions. Lowering [Ca2+]e, however, is known to increase the inactivation of voltage-gated cation channels, especially when the membrane is depolarized. Two hypotheses were tested: (1) lowering [Ca2+]e depresses force in normal muscles under conditions that depolarize the cell membrane; and (2) HyperKPP muscles have a greater sensitivity to low Ca2+-induced force depression because many fibers are depolarized, even at a normal [K+]e. In wild type muscles, lowering [Ca2+]e from 2.4 to 0.3 mM had little effect on tetanic force and membrane excitability at a normal K+ concentration of 4.7 mM, whereas it significantly enhanced K+-induced depression of force and membrane excitability. In HyperKPP muscles, lowering [Ca2+]e enhanced the K+-induced loss of force and membrane excitability not only at elevated [K+]e but also at 4.7 mM K+. Lowering [Ca2+]e increased the incidence of generating fast and transient contractures and gave rise to a slower increase in unstimulated force, especially in HyperKPP muscles. Lowering [Ca2+]e reduced the efficacy of salbutamol, a β2 adrenergic receptor agonist and a treatment for HyperKPP, to increase force at elevated [K+]e. Replacing Ca2+ by an equivalent concentration of Mg2+ neither fully nor consistently reverses the effects of lowering [Ca2+]e. These results suggest that the greater Ca2+ sensitivity of HyperKPP muscles primarily relates to (1) a greater effect of Ca2+ in depolarized fibers and (2) an increased proportion of depolarized HyperKPP muscle fibers compared with control muscle fibers, even at normal [K+]e.