has been reported in a single study to be the main driver of DUX4 protein-induced muscle cell death. The hypoxia-inducible factors (HIFs) are upregulated by DUX4 protein, possibly causing pathologic signaling leading to cell death. Another study found that DUX4 expression in muscle cells led to the recruitment and alteration of fibrous/fat progenitor cells, which helps explain why muscles become replaced by fat and fibrous tissue. A single study implicated RIPK3 in DUX4-mediated cell death. Muscle histology Unlike other muscular dystrophies, early muscle biopsies show only mild degrees of fibrosis, muscle fiber hypertrophy, and displacement of nuclei from myofiber peripheries (central nucleation). More often found is inflammation. There can be endomysial inflammation, primarily composed of CD8+ T-cells, although these cells do not seem to directly cause muscle fiber death. Endomysial blood vessels can be surrounded by inflammation, which is relatively unique to FSHD, and this inflammation contains CD4+ T-cells. Inflammation is succeeded by deposition of fat (fatty infiltration), then fibrosis. Individual muscle fibers can appear whorled, moth-eaten, and, especially, lobulated. Muscle involvement pattern Why certain muscles are preferentially affected in FSHD remains unknown. There are multiple trends of involvement seen in FSHD, possibly hinting at underlying pathophysiology. Individual muscles can weaken while adjacent muscles remain healthy. The right shoulder and arm muscles are more often affected than the left upper extremity muscles, a pattern also seen in Poland syndrome and hereditary neuralgic amyotrophy; this could reflect a genetic, developmental/anatomic, or functional-related mechanism. The deltoid is often spared, which is not seen in any other condition that affects the muscles around the scapula. Medical imaging (CT and MRI) have shown muscle involvement not readily apparent otherwise A single MRI study shows the teres major muscle to be commonly affected. The semimembranosus muscle, part of the hamstrings, is commonly affected, deemed by one author to be "the most frequently and severely affected muscle." Of the quadriceps muscles, the rectus femoris is preferentially affected Of the gastrocnemius, the medial section is preferentially affected; The iliopsoas, a hip flexor muscle, is very often spared. Retinopathy Tortuosity of the retinal arterioles, and less often microaneurysms and telangiectasia, are commonly found in FSHD. Abnormalities of the capillaries and venules are not observed. One theory for why the arterioles are selectively affected is that they contain smooth muscle. The degree of D4Z4 contraction correlates to the severity of tortuosity of arterioles. It has been hypothesized that retinopathy