Satellite cells are the myogenic stem and progenitor population found in skeletal muscle. These cells typically reside in a quiescent state until called upon to support repair, regeneration, or muscle growth. The activities of satellite cells are orchestrated by systemic hormones, autocrine and paracrine growth factors, and the composition of the basal lamina of the muscle fiber. Several key intracellular signaling events are initiated in response to changes in the local environment causing exit from quiescence, proliferation, and differentiation. Signals emanating from Notch, wingless-type mouse mammary tumor virus integration site family members, and transforming growth factor-β proteins mediate the reversible exit from growth 0 phase while those initiated by members of the fibroblast growth factor and insulin-like growth factor families direct proliferation and differentiation. Many of these pathways impinge upon the myogenic regulatory factors (MRF), myogenic factor 5, myogenic differentiation factor D, myogenin and MRF4, and the lineage determinate, Paired box 7, to alter transcription and subsequent satellite cell decisions. In the recent past, insight into mouse transgenic models has led to a firm understanding of regulatory events that control satellite cell metabolism and myogenesis. Many of these niche-regulated functions offer subtle differences from their counterparts in livestock pointing to the existence of species-specific controls. The purpose of this review is to examine the mechanisms that mediate large animal satellite cell activity and their relationship to those present in rodents.
Postexercise skeletal muscle repair is dependent on the actions of satellite cells (SCs). The signal(s) responsible for activation of these normally quiescent cells in the horse remain unknown. The objective of the experiment was to determine whether submaximal exercise or tributyrin (TB) supplementation is sufficient to stimulate SC activation. Adult geldings were fed a control diet (n = 6) or a diet containing 0.45% TB (n = 6). After 30 d, the geldings performed a single bout of submaximal exercise. Middle gluteal muscle biopsies and blood were collected on days −1, 1, 3, and 5 relative to exercise. Diet had no effect on any parameter of physical performance. Total RNA isolated from the gluteal muscle of TB fed geldings contained greater (P < 0.05) amounts of myogenin mRNA than controls. Satellite cell isolates from TB supplemented horses had a greater (P = 0.02) percentage of proliferating cell nuclear antigen immunopositive (PCNA+) SC than controls after 48 h in culture. Submaximal exercise was sufficient to increase (P < 0.05) the percentage of PCNA(+) cells in all isolates obtained during recovery period. No change in the amount of gluteal muscle Pax7 mRNA, a lineage marker of SCs, occurred in response to either diet or exercise. Our results indicate that both submaximal exercise and TB prime SCs for activation and cell cycle reentry but are insufficient to cause an increase in Pax7 expression during the recovery period.
Hepatocyte growth factor (HGF) signals mediate mouse skeletal muscle stem cell, or satellite cell (SC), reentry into the cell cycle and myoblast proliferation. Because the athletic horse experiences exercise-induced muscle damage, the objective of the experiment was to determine the effect of HGF on equine SC (eqSC) bioactivity. Fresh isolates of adult eqSC were incubated with increasing concentrations of HGF and the initial time to DNA synthesis was measured. Media supplementation with HGF did not shorten (P > 0.05) the duration of G0/G1 transition suggesting the growth factor does not affect activation. Treatment with 25 ng/mL HGF increased (P < 0.05) eqSC proliferation that was coincident with phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and AKT serine/threonine kinase 1 (AKT1). Chemical inhibition of the upstream effectors of ERK1/2 or AKT1 elicited no effect (P > 0.05) on HGF-mediated EdU incorporation. By contrast, treatment of eqSC with 2 µm Gö6983, a pan-protein kinase C (PKC) inhibitor, blocked (P < 0.05) HGF-initiated mitotic activity. Gene expression analysis revealed that eqSC express PKCα, -δ and -ε isoforms. Knockdown of PKCδ with a small interfering RNA (siRNA) prevented (P > 0.05) HGF-mediated EdU incorporation. The siPKCδ was specific to the kinase and did not affect (P > 0.05) expression of either PKCα or PKCε. Treatment of confluent eqSCs with 25 ng/mL HGF suppressed (P < 0.05) nuclear myogenin expression during the early stages of differentiation. These results demonstrate that HGF may not affect activation but can act as a mitogen and modest suppressor of differentiation.
Strenuous exercise can cause tissue damage, leading to an extended recovery period. To counteract delayed post-exercise recovery, a commercial product containing L-carnitine (AID) was tested in adult horses performing consecutive exercise tests to exhaustion. Fit Thoroughbreds were administered an oral bolus of placebo (CON) or AID prior to performing an exercise test to exhaustion (D1). The heart rate (HR) and fetlock kinematics were captured throughout the exercise test. Blood was collected before, 10 min and 1, 4 and 6 h relative to exercise for the quantification of cytokine (IL1β, IL8, IL10, TNFa) gene expression and lactate concentration. Horses performed a second exercise test 48 h later (D2), with all biochemical and physiological measures repeated. The results demonstrate that the horses receiving AID retained a greater (p < 0.05) amount of flexion in the front fetlock on D2 than the horses given CON. The horses presented a reduced (p < 0.05) rate of HR decline on D2 compared to that on D1. The expression of IL1β, IL8 and IL10 increased at 1 h post-exercise on D1 and returned to baseline by 6 h; the cytokine expression pattern was not duplicated on D2. These results provide evidence of disrupted cytokine expression, HR recovery and joint mobility in response to consecutive bouts of exhaustive exercise. Importantly, AID may accelerate recovery through an undetermined mechanism.
In equine sports, the rate of recovery after an exhaustive exercise session greatly affects the ability of the animal to perform subsequently, especially if the next exercise session occurs quickly. Carnitine participates in fatty acid delivery to the mitochondria and may facilitate muscle recovery post-exercise. The objective of the study was to determine the effects of a commercially available carnitine supplement (Renew, Platinum Performance, Buellton, CA) on adult The ability of Thoroughbred horses (16 geldings, 2 mares, 6.69 ± 0.49 years, 524.81 ± 10.07 kg, 5.66 ± 0.12 BCS) to perform successive bouts of exhaustive exercise. All horses participated in a moderate workload conditioning program for 6-weeks before testing. Horses received a ration of applesauce (30 mL, CON, n = 8) or ration of applesauce containing 19.6 g of the product (30 mL, AID, n = 8) 1 h before performing an incremental standardized exercise test (iSET) to exhaustion (day 1). Heart rate (HR) and gait biomechanics were recorded throughout the duration of the iSET. Blood was collected at 0, 10 min, 1, 4 and 6 h relative to exercise for the measurement of lactate and interleukin (IL) 1b, 8 and 10 mRNA content. for the measurement of lactate and interleukin (IL) 1b, IL8 and IL10 mRNA content. The AID was administered again at 1 h post-iSET after collection of the blood sample. All horses were rested for 24 h before repeating the iSET (day 3) with performance data and sample collection. The AID did not affect time to maximum HR, time to reach V200 or total gallop time during the iSET on day 1 or day 3. The rate of HR decline post iSET was slower (P < 0.05) for all horses on day 3 compared with day 1. Blood lactate concentration was not affected by AID or day. The right front limb posterior fetlock angle at full stance phase increased (P < 0.05) with speed for both CON and AID supplemented horses on day 1. Horses receiving AID demonstrated an increase (P < 0.05) in this measure at day 3 while no significant differences (P > 0.05) in posterior angle were detected in CON. Administration of AID did not affect whole blood IL1b, IL8 or IL10 mRNA content on day 1 or day 3. Consolidation of the data demonstrates increased (P < 0.05) expression of IL1b and IL8 mRNA during post-exercise recovery time on day 1 that was absent on day 3. Expression of IL10 was altered (P < 0.05) over time post-exercise on both days. Results of the experiment demonstrate that successive bouts of exercise affect the inflammatory response to exhaustion. Although AID did not affect IL gene expression, it did promote retention of flexion at the fetlock joint suggesting that carnitine products may facilitate recovery from strenuous exercise.
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