The chronic low-level inflammation associated with obesity is known to deleteriously affect muscle composition. However, the manner in which obesity leads to muscle loss has not been explored in detail or in an integrated manner following a short-term metabolic challenge. In this paper, we evaluated the relationships between compromised muscle integrity, diet, systemic inflammatory mediators, adipose tissue, and gut microbiota in male Sprague-Dawley rats. We show that intramuscular fat, fibrosis, and the number of pro-inflammatory cells increased by 3-days and was sustained across 28-days of high-fat high-sugar feeding compared to control-diet animals. To understand systemic contributors to muscle damage, dynamic changes in gut microbiota and serum inflammatory markers were evaluated. Data from this study links metabolic challenge to persistent compromise in muscle integrity after just 3-days, a finding associated with altered gut microbiota and systemic inflammatory changes. These data contribute to our understanding of early consequences of metabolic challenge on multiple host systems, which are important to understand as obesity treatment options are developed. Therefore, intervention within this early period of metabolic challenge may be critical to mitigate these sustained alterations in muscle integrity.