Circadian clock protein Bmal1 regulates respiratory motor plasticity in male rats.

Acute intermittent hypoxia (AIH) elicits respiratory motor plasticity in the phrenic, intercostal, and hypoglossal motor pools and has emerged as a promising therapeutic strategy to improve respiratory function in people with neuromuscular disorders that compromise breathing. Although we recently reported that time-of-day regulates moderate ([Formula: see text] ∼40-50 mmHg) AIH-induced respiratory motor plasticity, it is unknown whether diurnal effects on AIH-induced phrenic (pLTF) or ventilatory (vLTF) long-term facilitation are mediated via the endogenous circadian clock versus other factors. Since many biological rhythms are driven by the endogenous clock and clock genes (including the essential clock gene Bmal1) are rhythmically expressed in the phrenic motor system, we hypothesized that the molecular clock within respiratory motor neurons exerts time-of-day effects on pLTF and vLTF in Sprague Dawley rats (3-6 mo old males). Intrapleural injections of small-interfering RNAs (siRNAs) were used to selectively knock down Bmal1 within respiratory motor neurons by ∼30%. AIH consisting of 15, 1-min hypoxic episodes ([Formula: see text] = 0.09) was delivered in the midrest (i.e., light) or midactive (i.e., dark) phases, and pLTF (Δintegrated phrenic burst amplitude) and vLTF (ΔV̇e/V̇co