Muscle GPRC6A regulation of protein turnover with overload and disuse recovery - Skeletal muscle mass maintenance is critical for metabolic health and functional capacity and becomes a
challenge during forced immobility or sedentary behavior. Despite progress in understanding the molecular
drivers of load-induced muscle growth, there remains a need for novel approaches and different mechanistic
paradigms to enhance muscle recovery from atrophy. Although load-induced muscle growth and recovery from
disuse muscle atrophy involve protein accretion, the growth processes differ in the extent of the remodeling,
damage, and inflammation present. We will mechanistically investigate a novel regulatory paradigm involved in
skeletal muscle mass and metabolism regulation to improve our understanding of recovery from disuse atrophy
and identify therapeutic targets for treating low muscle mass in patients. GPRC6A is a G-protein-linked
receptor expressed in many tissues, including skeletal muscle, and has multiple ligands, including the peptide
osteocalcin. Ligand activation of GPRC6A improves glucose tolerance and peripheral insulin sensitivity and
prevents high-fat diet-induced hepatosteatosis in mice. GPRC6A knockout mice manifest metabolic syndrome,
loss of muscle mass, glucose intolerance, and insulin resistance. There is evidence that signaling initiated by
the skeletal muscle GPRC6A receptor can regulate muscle growth and metabolism. However, skeletal muscle
GPRC6A's role in disuse atrophy and recovery is not known. Our investigative team’s synergistic expertise in
GPRC6A function, metabolism, in vitro myotube growth, in vivo preclinical disuse and recovery models, and
muscle biology provides a unique opportunity to study this novel regulatory paradigm. Our project's expected
results hold substantial potential for identifying therapeutic targets to benefit muscle accretion in low muscle
mass patients. The proposed study will provide foundational evidence for novel therapeutic paradigms to
improve skeletal muscle load sensitivity linked to disuse atrophy and recovery. Genetic and pharmacological
approaches will investigate GPRC6A regulation of muscle mass accretion and contractile function. Our central
hypothesis is that loss of skeletal muscle GPRC6A signaling will attenuate recovery from disuse atrophy in
male and female mice. Furthermore, GPRC6A activation by Ocn will accelerate the recovery of mass,
metabolic properties, and contractile function. Aim 1 will investigate muscle GPRC6A’s role in myotube growth
and atrophy in vitro. Established models of high serum media and stretch-induced growth in additional to
stretch-release to examine myotube atrophy will be used to assess effects on stretch and serum-induced
growth. Aim 2 will evaluate the role of GPRC6A signaling in disuse atrophy and the load-induced recovery of
muscle mass and contractile and metabolic function in vivo. Normal cage ambulation after hindlimb
suspension-induced disuse will examine recovery from atrophy. Our results will provide the foundation for
novel therapeutic approaches that activate GPRC6A via ligands such as testosterone or other pharmaceutical
interventions.
