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Publications of the Week

pH-Gated Succinate Secretion Regulates Muscle Remodeling in Response to Exercise

By October 1, 2020No Comments

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This week we profile a recent publication in Cell from the laboratory of Dr. Edward Chouchani (pictured) at Dana-Farber.

Why did you decide to do this research project and what prior work led up to this latest paper?

We wanted to better understand how muscle cells communicate to the tissue environment to coordinate healthy adaptation that occurs during exercise. It is known that muscle adaptation to exercise requires paracrine signaling from contracting myofibers to non-myofibrillar cells resident in muscle tissue, but the identity of these signals is poorly defined.

Can you explain the methodology used in your paper? Why did you decide to adopt this approach?

Based on a rich prior literature, we knew that muscle adaptation to exercise occurs rapidly. For this reason, we hypothesized that selective release of metabolites could facilitate this type of regulation, since metabolite production and transport are regulated on rapid timescales. We therefore applied small molecule mass spectrometry approaches in mouse and human models of acute exercise to track accumulation of metabolites in the extracellular fluids of exercising muscle.

What were the most significant findings? How do they relate to what was already known about the subject?

We discovered that exercising muscle selectively releases the mitochondrial metabolite succinate. This selective release was unexpected because succinate is a ubiquitous decarboxylate metabolite that is thought to remain trapped within cells. However, during exercise muscle cells become transiently acidified, a bioenergetic consequence of exercise that has been known for decades. We found that because of its unusual chemical properties, succinate can become protonated in this slightly acidic environment, which transforms it from a decarboxylate to a monocarboxylate. In this protonated state, succinate is rendered a transport substrate for the monocarboxylate transporter MCT1, which facilitates pH-gated release.

Once released, succinate co-ordinates paracrine signaling through ligation of its cognate GPCR SUCNR1, which is expressed in a variety of non-myofibrillar cells resident in muscle tissue. This newfound succinate secretion pathway is critical for physiological adaptations to exercise in mice, including remodeling of muscle innervation, muscle ECM, and improvements in muscle strength.

How do you plan to take this work forward? What are the implications for future research?

Based on these findings we propose a general model whereby intracellular energetic status can be communicated systemically through pH-gated succinate release, which could be broadly relevant in other physiological contexts of cellular acidosis. We are eager to explore the implications of this model in other states of physiological hypoxia such as cancer. Moreover, since small molecule agonists have been developed for SUCNR1, we are interested to test whether these molecules can recapitulate any of muscle the remodeling effects initiated by exercise-mediated release of endogenous succinate.

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