Acute molecular response of mouse hindlimb muscles to chronic stimulation

Abstract

Stimulation of the mouse hindlimb via the sciatic nerve was performed for a 4-h period to investigate acute muscle gene activation in a model of muscle phenotype conversion. Initial force production (1.6 +/- 0.1 g/g body wt) declined 45% within 10 min and was maintained for the remainder of the experiment. Force returned to initial levels upon study completion. An immediate-early growth response was present in the extensor digitorum longus (EDL) muscle (FOS, JUN, activating transcription factor 3, and musculoaponeurotic fibrosarcoma oncogene) with a similar but attenuated pattern in the soleus muscle. Transcript profiles showed decreased fast fiber-specific mRNA (myosin heavy chains 2A and 2B, fast troponins T(3) and I, alpha-tropomyosin, muscle creatine kinase, and parvalbumin) and increased slow transcripts (myosin heavy chain-1beta/slow, troponin C slow, and tropomyosin 3y) in the EDL versus soleus muscles. Histological analysis of the EDL revealed glycogen depletion without inflammatory cell infiltration in stimulated versus control muscles, whereas ultrastructural analysis showed no evidence of myofiber damage after stimulation. Multiple fiber type-specific transcription factors (tea domain family member 1, nuclear factor of activated T cells 1, peroxisome proliferator-activated receptor-gamma coactivator-1alpha and -beta, circadian locomotor output cycles kaput, and hypoxia-inducible factor-1alpha) increased in the EDL along with transcription factors characteristic of embryogenesis (Kruppel-like factor 4; SRY box containing 17; transcription factor 15; PBX/knotted 1 homeobox 1; and embryonic lethal, abnormal vision). No established in vivo satellite cell markers or genes activated in our parallel experiments of satellite cell proliferation in vitro (cyclins A(2), B(2), C, and E(1) and MyoD) were differentially increased in the stimulated muscles. These results indicated that the molecular onset of fast to slow phenotype conversion occurred in the EDL within 4 h of stimulation without injury or satellite cell recruitment. This conversion was associated with the expression of phenotype-specific transcription factors from resident fiber myonuclei, including the activation of nascent developmental transcriptional programs.

Altered mRNA expression after long‐term soleus electrical stimulation training in humans with paralysis

“…A key determinant of skeletal myofiber type is PGC‐1α, which promotes the slow‐twitch, oxidative phenotype 17, 25. PGC‐1α expression is increased by exercise in human soleus and vastus lateralis muscles26, 27 and by electrical stimulation training in mouse extensor digitorum 28. Perhaps not surprisingly, we found that training increased the level of mRNA that encodes PGC‐1α (Fig.…”

Nitric oxide synthase inhibition prevents activity‐induced calcineurin–NFATc1 signalling and fast‐to‐slow skeletal muscle fibre type conversions

“…In response to various contractile demands such as exercise, skeletal muscle demonstrates remarkable adaptability or plasticity that is largely dictated by changes in motor neuron activity. For example, chronic low‐frequency electrical stimulation (CLFS; 10 Hz) of the motor nerve mimics the tonic firing pattern typical of slow motor neurons (Hennig & Lomo, 1985) and induces maximal faster‐to‐slower fibre type transformations in the absence of skeletal muscle injury in the rat model (Putman et al 1999, 2000, 2001; Martins et al 2006; LaFramboise et al 2009). This fibre type transformation generally follows the ‘next nearest‐neighbour’ rule where fibre types undergo a predictable pattern of transformation in the direction of fast type IIB→IID(X)→IIA→ slow type I (Pette & Vrbová, 1999; Pette & Staron, 2000).…”

Activating transcription factor 3 attenuates chemokine and cytokine expression in mouse skeletal muscle after exercise and facilitates molecular adaptation to endurance training

“…As a physiological stressor, exercise induces atf3 expression in the skeletal muscle of mice, rats, and humans (10)(11)(12)(13)(14), as do other models of muscular activity, such as hind limb unloading/reloading, electrical stimulation of the sciatic nerve, functional overload, and eccentric contractions (15)(16)(17)(18)(19). Intriguingly, atf3 upregulation is usually one the highest among all the genes examined.…”