Date of Award

January 2026

Document Type

Thesis

Degree Name

Master of Public Health (MPH)

Department

School of Public Health

First Advisor

Melinda L L. Irwin

Second Advisor

Tamas L. Horvath

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a dominant pharmacological intervention for obesity and type 2 diabetes mellitus. However, their effects on skeletal muscle function remain incompletely characterized. This review addresses that gap by synthesizing evidence from both human clinical studies and rodent models, evaluating the effects of GLP-1 RAs on skeletal muscle function across diverse populations and pathological contexts.

A systematic search identified eight human studies and eighteen rodent studies meeting inclusion criteria. In human populations with obesity, type 2 diabetes mellitus (T2DM), or related metabolic syndrome, the impact of GLP-1 RA therapy on skeletal muscle function was heterogeneous. Nonetheless, functional capacity was frequently preserved or marginally improved despite significant reductions in absolute muscle mass. Older cohorts demonstrated greater vulnerability to functional decline, while high-protein dietary composition appeared to mitigate therapy-associated functional impairment.

Across eighteen preclinical studies, a predominantly positive but highly context-dependent effect on skeletal muscle function was observed. The evidence collectively argues against a uniform anabolic mechanism, instead supporting a rescue-dominant paradigm in which GLP-1 RA preferentially restores function in pathologically compromised tissue rather than enhancing baseline muscle performance. Furthermore, findings from the rodent models sheds light on the potential mechanisms of the mass-function dissociation observed as a result of GLP-1 RA treatment.

The two bodies of evidence converge on a central conclusion: GLP-1 RA's effects on skeletal muscle function are not an intrinsic property of the drug class, but a state-dependent outcome contingent on numerous factors, including pathological context, age, tissue metabolic state, and lifestyle factors. These findings demonstrate the importance of incorporating muscle functional assessment into the routine outcome measure in GLP-1 RA therapy. Future research must prioritize powered randomized controlled trials with functional endpoints, as well as mechanistic studies bridging the fiber-type and mitochondrial findings observed preclinically to human muscle physiology.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 03/16/2027

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