Alcohol and the skeletal muscle clock

Project Summary/Abstract Alcohol is a well-known myotoxin that with sustained use can culminate in alcohol-associated muscle disease (AAMD), characterized by muscle weakness and functional decline, along with metabolic impairments and decreases in muscle size (i.e., mass), that culminate in reduced quality of life. While mechanisms regulating

protein balance have previously been implicated in AAMD development, additional pathways require exploration to develop new therapeutic targets as none currently exist. Our previous work indicates that both binge and chronic alcohol intoxication disrupt the core molecular clock within the skeletal muscle however,

whether clock disruption contributes to the etiology of AAMD remains unknown. Overall, the long-term goal is to mechanistically determine whether alcohol’s influence on the skeletal muscle core clock impacts alcohol- associated disease risk, as well as to determine how alcohol modulates the core clock so that targeting of

specific clock components can be used as therapeutic interventions. Specifically, skeletal muscle contractile strength is reduced by chronic alcohol use in a manner that closely parallels that caused by skeletal muscle- specific core molecular clock disruption (in the absence of alcohol), inferring that alcohol-induced disruption in

the core clock may be responsible for AAMD associated weakness. Therefore, Specific Aim 1 of the current proposal is to determine whether disruption to the skeletal muscle core molecular clock contributes to the decreases in contractile function caused by chronic alcohol use. The second Aim will be to determine how

alcohol consumption causes skeletal muscle core clock disruption so that preventative interventions can be developed. Specific Aim 1 will use a mouse model of muscle-specific circadian pathway dysfunction caused by the inducible deletion of the core clock gene Brain muscle arnt like-1 (Bmal1) to determine the role of the

skeletal muscle clock on contractile function during alcohol intoxication. Specific Aim 2 will define the role of alcohol and alcohol-related factors in the disruption of the skeletal muscle clock by investigating the influence of both peripheral circulating factors produced during alcohol metabolism and the role of the central (i.e. brain-

specific) administration of alcohol on the circadian function within the skeletal muscle. These research questions will be addressed by using a variety of physiological models paired with in vitro, in vivo and in situ techniques. This investigation will be the first of its kind in the study of the effects of alcohol on core clock

function in the muscle and one of the few to consider the influence of peripheral tissues in the development of AAMD. Lastly, it will lay the foundation for continued mechanistic investigations to determine the role of the core molecular clock in AAMD.